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Yakut A. Gut microbiota in the development and progression of chronic liver diseases: Gut microbiota-liver axis. World J Hepatol 2025; 17:104167. [PMID: 40177197 PMCID: PMC11959663 DOI: 10.4254/wjh.v17.i3.104167] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2024] [Revised: 01/28/2025] [Accepted: 02/25/2025] [Indexed: 03/26/2025] Open
Abstract
The gut microbiota (GM) is a highly dynamic ecology whose density and composition can be influenced by a wide range of internal and external factors. Thus, "How do GM, which can have commensal, pathological, and mutualistic relationships with us, affect human health?" has become the most popular research issue in recent years. Numerous studies have demonstrated that the trillions of microorganisms that inhabit the human body can alter host physiology in a variety of systems, such as metabolism, immunology, cardiovascular health, and neurons. The GM may have a role in the development of a number of clinical disorders by producing bioactive peptides, including neurotransmitters, short-chain fatty acids, branched-chain amino acids, intestinal hormones, and secondary bile acid conversion. These bioactive peptides enter the portal circulatory system through the gut-liver axis and play a role in the development of chronic liver diseases, cirrhosis, and hepatic encephalopathy. This procedure is still unclear and quite complex. In this study, we aim to discuss the contribution of GM to the development of liver diseases, its effects on the progression of existing chronic liver disease, and to address the basic mechanisms of the intestinal microbiota-liver axis in the light of recent publications that may inspire the future.
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Affiliation(s)
- Aysun Yakut
- Department of Gastroenterology, İstanbul Medipol University Sefakoy Health Practice Research Center, İstanbul 38000, Türkiye.
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Zhang Y, Ma J, Li P, Lu K, Han Y, Hu X, Fang X, Wang X, Zhang Y. Fatty acid metabolism shapes immune responses in chronic lymphocytic leukemia. Biomark Res 2025; 13:42. [PMID: 40075418 PMCID: PMC11905569 DOI: 10.1186/s40364-025-00753-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2024] [Accepted: 02/26/2025] [Indexed: 03/14/2025] Open
Abstract
BACKGROUND Fatty acids serve as a crucial energy source for tumor cells during the progression of chronic lymphocytic leukemia (CLL). The present study aims to elucidate the characteristics of fatty acid metabolism (FAM) in CLL, construct a related prognostic score, and investigate the regulatory role and mechanisms of FAM in CLL development. METHODS Bulk RNA sequencing data from CLL patients and healthy controls were analyzed to identify differentially expressed fatty acid metabolic genes. FAM-score was constructed using Cox-LASSO regression and validated. Single-cell RNA sequencing was used to analyze the expression of key FAM genes in CLL immune cell subsets and investigate cellular communication. Functional assays, including cell viability, drug sensitivity, and oxygen consumption assays, were performed to assess the impact of fatty acid oxidation (FAO) inhibition on CLL cells. RESULTS Three FAM-related genes (LPL, SOCS3, CNR1) were identified with independent prognostic significance to construct the risk score. The FAM-score demonstrated superior prognostic performance compared to the Binet stage and was associated with established clinical prognostic markers. Single-cell analysis revealed distinct expression patterns of LPL, SOCS3, and CNR1 across CLL immune cell subsets. Cellular communication analysis highlighted the regulatory role of distinct B cell and Treg subsets in the CLL microenvironment. CLL patients with high FAM-score displayed distinct immune infiltration patterns, with increased FAO pathway activity. Inhibition of FAO reduced CLL cell viability, synergistically enhanced the efficacy of the PI3K inhibitor idelalisib. CONCLUSION The present study constructed a prognostic risk score based on FAM gene expression, revealing related immune phenotypic differences and exploring the regulatory role of FAO in CLL development. Targeting fatty acid metabolism potentially modulates the CLL immune microenvironment and synergistically enhances the efficacy of PI3K inhibitors.
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Affiliation(s)
- Yang Zhang
- Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, No.324, Jingwu Road, Jinan, Shandong, 250021, China
| | - Jun Ma
- Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, No.324, Jingwu Road, Jinan, Shandong, 250021, China
| | - Peipei Li
- Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, No.324, Jingwu Road, Jinan, Shandong, 250021, China
| | - Kang Lu
- Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, No.324, Jingwu Road, Jinan, Shandong, 250021, China
| | - Yang Han
- Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, No.324, Jingwu Road, Jinan, Shandong, 250021, China
| | - Xinting Hu
- Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, No.324, Jingwu Road, Jinan, Shandong, 250021, China
| | - Xiaosheng Fang
- Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, No.324, Jingwu Road, Jinan, Shandong, 250021, China
| | - Xin Wang
- Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, No.324, Jingwu Road, Jinan, Shandong, 250021, China
| | - Ya Zhang
- Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, No.324, Jingwu Road, Jinan, Shandong, 250021, China.
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Maccioni L, Dvorácskó S, Godlewski G, Cinar R, Iyer MR, Gao B, Kunos G. Gut cannabinoid receptor 1 regulates alcohol binge-induced intestinal permeability. EGASTROENTEROLOGY 2025; 3:e100173. [PMID: 40124989 PMCID: PMC11927431 DOI: 10.1136/egastro-2024-100173] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/09/2024] [Accepted: 01/29/2025] [Indexed: 03/25/2025]
Abstract
Background Endocannabinoids acting via cannabinoid receptor 1 (CB1R) can elicit increased intestinal permeability (a condition also called 'leaky gut'). Alcohol binge can adversely affect digestive functions, including intestinal permeability; however, the underlying mechanisms remain incompletely understood. The current study aimed at examining whether CB1R is involved in alcohol binge-induced intestinal permeability. Methods We developed intestinal epithelial-specific CB1R knockout (CB1IEC-/-) mice and evaluated the in vivo contribution of gut CB1R in alcohol binge-induced intestinal permeability. Results Alcohol binge increased anandamide levels in the proximal small intestine in association with increased intestinal permeability. Radioligand binding and functional assays confirmed that the genetic deletion of intestinal epithelial CB1R did not alter the density or functionality of CB1R in the brain. Additionally, a peripheral CB1R antagonist, (S)-MRI-1891 (INV-202/monlunabant), exhibited comparable binding affinity to CB1R in brain homogenates. An acute oral administration of (S)-MRI-1891 (3 mg/kg) reduced alcohol binge-induced intestinal permeability in littermate control CB1f/f (CB1 floxed/floxed) mice but had no effect in CB1IEC-/- mice, underscoring the role of intestinal CB1R in this phenomenon. Mechanistically, we found that alcohol activated intestinal epithelial CB1R-ERK1/2 pathway with subsequent downregulation of tight junction proteins and reduction in villi length. In addition, targeting intestinal CB1R and downstream ERK1/2 was able to reverse this process, with subsequent upregulation of tight junction proteins and increased villi length, thus improving gut barrier function. Despite the effects on intestinal permeability, deletion of intestinal CB1R did not significantly affect metabolic parameters and liver disease. Conclusion Our findings suggest that alcohol promotes leaky gut via the activation of gut epithelial CB1R and demonstrate that inhibition of CB1R with peripheral-restricted selective CB1R antagonists can prevent alcohol binge-induced intestinal permeability.
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Affiliation(s)
- Luca Maccioni
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA
- Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA
| | - Szabolcs Dvorácskó
- Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA
- Section on Fibrotic Disorders, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA
- Section on Medicinal Chemistry, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA
- Laboratory of Biomolecular Structure and Pharmacology, HUN-REN Biological Research Centre Szeged, Institute of Biochemistry, Szeged, Hungary
| | - Grzegorz Godlewski
- Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA
| | - Resat Cinar
- Section on Fibrotic Disorders, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA
| | - Malliga R Iyer
- Section on Medicinal Chemistry, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA
| | - Bin Gao
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA
| | - George Kunos
- Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA
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Faulkner ML, Farokhnia M, Lee MR, Farinelli L, Browning BD, Abshire K, Daurio AM, Munjal V, Deschaine SL, Boukabara SR, Fortney C, Sherman G, Schwandt M, Akhlaghi F, Momenan R, Ross TJ, Persky S, Leggio L. A randomized, double-blind, placebo-controlled study of a GHSR blocker in people with alcohol use disorder. JCI Insight 2024; 9:e182331. [PMID: 39704175 PMCID: PMC11665556 DOI: 10.1172/jci.insight.182331] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2024] [Accepted: 10/30/2024] [Indexed: 12/21/2024] Open
Abstract
BACKGROUNDStudies have demonstrated the role of ghrelin in alcohol-related behaviors and consumption. Blockade of the growth hormone secretagogue receptor (GHSR), which is the ghrelin receptor, has been shown to decrease alcohol drinking and reward-related behaviors across several animal models. We previously conducted a human study testing a GHSR inverse agonist/competitive antagonist, PF-5190457, in individuals who are heavy drinkers and showed its safety when coadministered with alcohol. Here, we conducted a phase IIa experimental medicine study in patients with alcohol use disorder (AUD) to investigate the effects of PF-5190457 on alcohol- and food-related outcomes.METHODSForty-two individuals with AUD (n = 29 completers) participated in a randomized, double-blind, placebo-controlled study where they received PF-5190457 100mg b.i.d. (or placebo) in 2 counterbalanced, within-subject stages. Participants completed an alcohol cue-reactivity (CR) experiment in a bar-like laboratory and a virtual food choice experiment in a cafeteria-like virtual reality (VR) environment. A subset of participants (n = 12) performed a CR task during a brain functional MRI (fMRI) experiment.RESULTSPF-5190457 did not reduce cue-elicited alcohol craving. PF-5190457 reduced virtual calories selected (P = 0.04) in the VR environment. PF-5190457 did not influence neural activation during CR task in the fMRI experiment.CONCLUSIONThis study provides human evidence of the role of GHSR blockade in behaviors related to food selection and highlights the need for future investigations into targeting the ghrelin system in AUD.TRIAL REGISTRATIONClinicalTrials.gov (accession no. NCT02707055).FUNDINGNIDA and NIAAA ZIA-DA000635; National Center for Advancing Translational Sciences UH2/UH3-TR000963.
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Affiliation(s)
- Monica L. Faulkner
- Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, Translational Addiction Medicine Branch, National Institute on Drug Abuse (NIDA) Intramural Research Program, National Institute on Alcohol Abuse and Alcoholism (NIAAA) Division of Intramural Clinical and Biological Research, NIH, Baltimore and Bethesda, Maryland, USA
| | - Mehdi Farokhnia
- Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, Translational Addiction Medicine Branch, National Institute on Drug Abuse (NIDA) Intramural Research Program, National Institute on Alcohol Abuse and Alcoholism (NIAAA) Division of Intramural Clinical and Biological Research, NIH, Baltimore and Bethesda, Maryland, USA
- Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA
| | - Mary R. Lee
- Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, Translational Addiction Medicine Branch, National Institute on Drug Abuse (NIDA) Intramural Research Program, National Institute on Alcohol Abuse and Alcoholism (NIAAA) Division of Intramural Clinical and Biological Research, NIH, Baltimore and Bethesda, Maryland, USA
| | - Lisa Farinelli
- Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, Translational Addiction Medicine Branch, National Institute on Drug Abuse (NIDA) Intramural Research Program, National Institute on Alcohol Abuse and Alcoholism (NIAAA) Division of Intramural Clinical and Biological Research, NIH, Baltimore and Bethesda, Maryland, USA
| | - Brittney D. Browning
- Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, Translational Addiction Medicine Branch, National Institute on Drug Abuse (NIDA) Intramural Research Program, National Institute on Alcohol Abuse and Alcoholism (NIAAA) Division of Intramural Clinical and Biological Research, NIH, Baltimore and Bethesda, Maryland, USA
| | - Kelly Abshire
- Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, Translational Addiction Medicine Branch, National Institute on Drug Abuse (NIDA) Intramural Research Program, National Institute on Alcohol Abuse and Alcoholism (NIAAA) Division of Intramural Clinical and Biological Research, NIH, Baltimore and Bethesda, Maryland, USA
| | - Allison M. Daurio
- Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, Translational Addiction Medicine Branch, National Institute on Drug Abuse (NIDA) Intramural Research Program, National Institute on Alcohol Abuse and Alcoholism (NIAAA) Division of Intramural Clinical and Biological Research, NIH, Baltimore and Bethesda, Maryland, USA
| | - Vikas Munjal
- Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, Translational Addiction Medicine Branch, National Institute on Drug Abuse (NIDA) Intramural Research Program, National Institute on Alcohol Abuse and Alcoholism (NIAAA) Division of Intramural Clinical and Biological Research, NIH, Baltimore and Bethesda, Maryland, USA
| | - Sara L. Deschaine
- Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, Translational Addiction Medicine Branch, National Institute on Drug Abuse (NIDA) Intramural Research Program, National Institute on Alcohol Abuse and Alcoholism (NIAAA) Division of Intramural Clinical and Biological Research, NIH, Baltimore and Bethesda, Maryland, USA
| | - Selim R. Boukabara
- Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, Translational Addiction Medicine Branch, National Institute on Drug Abuse (NIDA) Intramural Research Program, National Institute on Alcohol Abuse and Alcoholism (NIAAA) Division of Intramural Clinical and Biological Research, NIH, Baltimore and Bethesda, Maryland, USA
| | - Christopher Fortney
- Immersive Simulation Program, Social and Behavioral Research Branch, National Human Genome Research Institute (NHGRI), NIH, Bethesda, Maryland, USA
| | - Garrick Sherman
- Office of the Clinical Director, NIDA, Intramural Research Program, NIH, Baltimore, Maryland, USA
| | - Melanie Schwandt
- Office of the Clinical Director, NIAAA Division of Intramural Clinical and Biological Research, NIH, Bethesda, Maryland, USA
| | - Fatemeh Akhlaghi
- Clinical Pharmacokinetics Research Laboratory, Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, Rhode Island, USA
| | - Reza Momenan
- Clinical NeuroImaging Research Core, NIAAA, NIH, Bethesda, Maryland, USA
| | - Thomas J. Ross
- Neuroimaging Core, NIDA Intramural Research Program, NIH, Baltimore, Maryland, USA
| | - Susan Persky
- Immersive Simulation Program, Social and Behavioral Research Branch, National Human Genome Research Institute (NHGRI), NIH, Bethesda, Maryland, USA
| | - Lorenzo Leggio
- Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, Translational Addiction Medicine Branch, National Institute on Drug Abuse (NIDA) Intramural Research Program, National Institute on Alcohol Abuse and Alcoholism (NIAAA) Division of Intramural Clinical and Biological Research, NIH, Baltimore and Bethesda, Maryland, USA
- Center for Alcohol and Addiction Studies, Department of Behavioral and Social Sciences, Brown University, Providence, Rhode Island, USA
- Division of Addiction Medicine, Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA
- Department of Neuroscience, Georgetown University Medical Center, Washington DC, USA
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Saenz C, Fernandez G, Llovera R, Tolosa MJ, Cantel S, Fehrentz JA, Mackie K, Leggio L, Zigman J, De Francesco PN, Perello M. Growth hormone secretagogue receptor and cannabinoid receptor type 1 intersection in the mouse brain. Brain Struct Funct 2024; 230:15. [PMID: 39702649 PMCID: PMC11659360 DOI: 10.1007/s00429-024-02876-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2024] [Accepted: 10/14/2024] [Indexed: 12/21/2024]
Abstract
The growth hormone secretagogue receptor (GHSR) and the cannabinoid receptor type 1 (CB1R) are G-protein coupled receptors highly expressed in the brain and involved in critical regulatory processes, such as energy homeostasis, appetite control, reward, and stress responses. GHSR mediates the effects of both ghrelin and liver-expressed antimicrobial peptide 2, while CB1R is targeted by cannabinoids. Strikingly, both receptors mediate their effects by acting on common brain areas and their individual roles have been well characterized. However, the potential for their co-expression in the same neuronal subsets remains largely unexplored. Here, we aim to map the cell populations where GHSR and CB1R might converge, hypothesizing that their co-expression in specific brain circuits could mediate integrated physiological responses. By utilizing two complementary labeling techniques-GHSR-eGFP mice and Fr-ghrelin labeling of GHSR+ cells-along with specific CB1R immunostaining, we sought to visualize and quantify potential areas of overlap. Also, we analyzed several cell RNA sequencing datasets to estimate the fraction of brain cells expressing both GPCRs and their phenotype. Our neuroanatomical studies revealed evident overlap of GHSR+ and CB1R+ signals in specific neuronal subsets mainly located in the cerebral cortex, hippocampus and the amygdala. Transcriptomic analysis revealed specific subsets of Ghsr+/Cnr1+ glutamatergic neurons in the hippocampus and amygdala, as well as different subtypes of Ghsr+/Cnr1+ neurons in the midbrain, hypothalamus, pons, and medulla. Thus, we revealed that GHSR and CB1R interact differentially across specific regions of the mouse brain, providing new insights into how these receptors' actions are integrated. Current findings may open new avenues for dual therapeutic interventions in metabolic disorders, obesity, and psychiatric conditions.
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Affiliation(s)
- Camila Saenz
- Laboratory of Neurophysiology of the Multidisciplinary Institute of Cell Biology [IMBICE, Argentine Research Council (CONICET) and Scientific Research Commission, Province of Buenos Aires (CIC-PBA), National University of La Plata], La Plata, Buenos Aires, Argentina
| | - Gimena Fernandez
- Laboratory of Neurophysiology of the Multidisciplinary Institute of Cell Biology [IMBICE, Argentine Research Council (CONICET) and Scientific Research Commission, Province of Buenos Aires (CIC-PBA), National University of La Plata], La Plata, Buenos Aires, Argentina
| | - Ramiro Llovera
- Laboratory of Neurophysiology of the Multidisciplinary Institute of Cell Biology [IMBICE, Argentine Research Council (CONICET) and Scientific Research Commission, Province of Buenos Aires (CIC-PBA), National University of La Plata], La Plata, Buenos Aires, Argentina
| | - María J Tolosa
- Laboratory of Neurophysiology of the Multidisciplinary Institute of Cell Biology [IMBICE, Argentine Research Council (CONICET) and Scientific Research Commission, Province of Buenos Aires (CIC-PBA), National University of La Plata], La Plata, Buenos Aires, Argentina
| | - Sonia Cantel
- Institut des Biomolécules Max Mousseron, Univ Montpellier, CNRS, ENSCM, Montpellier, France
| | - Jean-Alain Fehrentz
- Institut des Biomolécules Max Mousseron, Univ Montpellier, CNRS, ENSCM, Montpellier, France
| | - Kenneth Mackie
- Department of Psychological & Brain Sciences, Indiana University, Bloomington Indiana, USA
| | - Lorenzo Leggio
- Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, Translational Addiction Medicine Branch, Intramural Research Program and National Institute on Alcohol Abuse and Alcoholism Division of Intramural Clinical and Biological Research, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD, USA
| | - Jeffrey Zigman
- Center for Hypothalamic Research and Division of Endocrinology & Metabolism, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Pablo N De Francesco
- Laboratory of Neurophysiology of the Multidisciplinary Institute of Cell Biology [IMBICE, Argentine Research Council (CONICET) and Scientific Research Commission, Province of Buenos Aires (CIC-PBA), National University of La Plata], La Plata, Buenos Aires, Argentina.
| | - Mario Perello
- Laboratory of Neurophysiology of the Multidisciplinary Institute of Cell Biology [IMBICE, Argentine Research Council (CONICET) and Scientific Research Commission, Province of Buenos Aires (CIC-PBA), National University of La Plata], La Plata, Buenos Aires, Argentina.
- Department of Surgical Sciences, Functional Pharmacology and Neuroscience, University of Uppsala, Uppsala, Sweden.
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Jerlhag E. Ghrelin system and GLP-1 as potential treatment targets for alcohol use disorder. INTERNATIONAL REVIEW OF NEUROBIOLOGY 2024; 178:401-432. [PMID: 39523062 DOI: 10.1016/bs.irn.2024.07.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/16/2024]
Abstract
Peptides of the gut-brain axis have gained recent attention as potential treatment targets for addiction. While the number of gut-brain peptides is vast, ghrelin and glucagon-like peptide-1 (GLP-1) have been suggested as important players. Ghrelin is traditionally considered an orexigenic peptide, but recent studies found that it increases alcohol intake in rodents and craving for alcohol in humans. Additionally, suppression of the ghrelin receptor attenuates alcohol-related responses in animal models reflecting alcohol use disorder (AUD). For instance, a lower alcohol intake, suppressed motivation to consume alcohol, and attenuated reward from alcohol is observed after ghrelin receptor antagonism treatment. On a similar note, a partial ghrelin receptor agonist prevents hangover symptoms in humans. When it comes to the anorexigenic peptide GLP-1, agonists of its receptor are approved to treat diabetes type 2 and obesity. Extensive preclinical studies have revealed that these GLP-1 receptor agonists reduce alcohol intake, suppress the motivation to consume alcohol, and prevent relapse drink, with effects tentatively associated with a reduced alcohol-induced reward. These preclinical findings have to some extent been varied in humans, as GLP-1 receptor agonists decrease alcohol intake in overweight patients with AUD. Furthermore, genetic variations in either the genes encoding for pre-pro-ghrelin, GHSR, GLP-1, or its receptor, are associated with AUD and heavy alcohol drinking. While central mechanisms appear to modulate the ability of either ghrelin or GLP-1 to regulate alcohol-related responses the exact mechanisms have not been defined. Taken together these preclinical and clinical data imply that gut-brain peptides participate in the addiction process and should be considered as potential targets for AUD treatment.
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Affiliation(s)
- Elisabet Jerlhag
- Institute of Neuroscience and Physiology, Department of Pharmacology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
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Wu Y, Huang J, Liu L, Zhang X, Zhang W, Li Q. CircHIPK3/miR-124 affects angiogenesis in early-onset preeclampsia via CPT1A-mediated fatty acid oxidation. J Mol Med (Berl) 2024; 102:1037-1049. [PMID: 38904677 DOI: 10.1007/s00109-024-02461-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2023] [Revised: 03/22/2024] [Accepted: 06/07/2024] [Indexed: 06/22/2024]
Abstract
Multiple theories have been proposed to explain the pathogenesis of early-onset preeclampsia (EOPE), and angiogenic dysfunction is an important part of this pathogenesis. Carnitine palmitoyltransferase (CPT1A) is a key rate-limiting enzyme in the metabolic process of fatty acid oxidation (FAO). FAO regulates endothelial cell (EC) proliferation during vascular germination and is also essential for ab initio deoxyribonucleotide synthesis, but its role in EOPE needs to be further elucidated. In the present study, we investigated its functional role in EOPE by targeting the circHIPK3/miR-124-3p/CPT1A axis. In our study, reduced expression of circHIPK3 and CPT1A and increased expression of miR-124-3p in placental tissues from patients with EOPE were associated with EC dysfunction. Here, we confirmed that CPT1A regulates fatty acid oxidative activity, cell proliferation, and tube formation in ECs by regulating FAO. Functionally, knockdown of circHIPK3 suppressed EC angiogenesis by inhibiting CPT1A-mediated fatty acid oxidative activity, which was ameliorated by CPT1A overexpression. In addition, circHIPK3 regulates CPT1A expression by sponging miR-124-3p. Hence, circHIPK3 knockdown reduced fatty acid oxidation in ECs by sponging miR-124-3p in a CPT1A-dependent manner and inhibited EC proliferation and tube formation, which may have led to aberrant angiogenesis in EOPE. Thus, strategies targeting CPT1A-driven FAO may be promising approaches for the treatment of EOPE. KEY MESSAGES: Decreased Carnitine palmitoyltransferase (CPT1A) expression in preeclampsia(PE). CPT1A overexpression promotes FAO activity and tube formation in ECs. CircHIPK3 can affect CPT1A expression and impaire angiogenesis of EOPE. CircHIPK3 regulates CPT1A expression by acting as a ceRNA of miR-124-3p in HUVECs. Confirming the effect of circHIPK3/miR-124-3p/CPT1A axis on EOPE.
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Affiliation(s)
- Yanying Wu
- Department of Obstetrics, Xiangya Hospital Central South University, Changsha, China
| | - Jingrui Huang
- Department of Obstetrics, Xiangya Hospital Central South University, Changsha, China
- Hunan Engineering Research Center of Early Life Development and Disease Prevention, Changsha, China
| | - Lijuan Liu
- Department of Obstetrics, Xiangya Hospital Central South University, Changsha, China
| | - Xiaowen Zhang
- Department of Obstetrics, Xiangya Hospital Central South University, Changsha, China
| | - Weishe Zhang
- Department of Obstetrics, Xiangya Hospital Central South University, Changsha, China.
- Hunan Engineering Research Center of Early Life Development and Disease Prevention, Changsha, China.
| | - Qi Li
- Institute of Reproductive Medicine Center, Xiangya Hospital Central South University, Changsha, China.
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8
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Wang C, Yan J, Du K, Liu S, Wang J, Wang Q, Zhao H, Li M, Yan D, Zhang R, Yang F. Intestinal microbiome dysbiosis in alcohol-dependent patients and its effect on rat behaviors. mBio 2023; 14:e0239223. [PMID: 37962470 PMCID: PMC10746284 DOI: 10.1128/mbio.02392-23] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2023] [Accepted: 10/03/2023] [Indexed: 11/15/2023] Open
Abstract
IMPORTANCE Intestinal microbiome dysbiosis is associated with psychiatric disease through the "microbiota-gut-brain" axis. Here, we revealed that there was obvious intestinal microbiome (including bacterial and fungal) dysbiosis in alcohol-dependent patients. Alcohol consumption seriously disturbs the gut equilibrium between bacteria and fungi, reduces the interactions among bacterial-fungal trans-kingdom, and increases intestinal permeability. Gut microbiota should be considered as a whole to study the development of alcohol dependence. The gut microbiome of alcohol-dependent patients increased the anxiety- and depression-like behavior in rats. The gut microbiota dysbiosis may promote the development of alcohol dependence by regulating the endogenous cholecystokinin (CCK) and related receptors. Hence, regulating the balance of gut microbiota and the endogenous CCK may be a potential strategy for reducing the risk of relapse in alcohol addiction patients.
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Affiliation(s)
- Chuansheng Wang
- The Second Affiliated Hospital of Xinxiang Medical University, Henan Key Laboratory of Biological Psychiatry, Xinxiang Medical University, Xinxiang, China
| | - Junli Yan
- The Second Affiliated Hospital of Xinxiang Medical University, Henan Key Laboratory of Biological Psychiatry, Xinxiang Medical University, Xinxiang, China
| | - Keda Du
- The Second Affiliated Hospital of Xinxiang Medical University, Henan Key Laboratory of Biological Psychiatry, Xinxiang Medical University, Xinxiang, China
| | - Shuai Liu
- The Second Affiliated Hospital of Xinxiang Medical University, Henan Key Laboratory of Biological Psychiatry, Xinxiang Medical University, Xinxiang, China
| | - Jiali Wang
- The Second Affiliated Hospital of Xinxiang Medical University, Henan Key Laboratory of Biological Psychiatry, Xinxiang Medical University, Xinxiang, China
| | - Qi Wang
- The Second Affiliated Hospital of Xinxiang Medical University, Henan Key Laboratory of Biological Psychiatry, Xinxiang Medical University, Xinxiang, China
| | - Huajie Zhao
- Department of Pathogeny, School of Basic Medical Science, Xinxiang Medical University, Xinxiang, China
| | - Min Li
- Department of Pathogeny, School of Basic Medical Science, Xinxiang Medical University, Xinxiang, China
| | - Dong Yan
- Department of Pathogeny, School of Basic Medical Science, Xinxiang Medical University, Xinxiang, China
| | - Ruiling Zhang
- The Second Affiliated Hospital of Xinxiang Medical University, Henan Key Laboratory of Biological Psychiatry, Xinxiang Medical University, Xinxiang, China
| | - Fan Yang
- Department of Pathogeny, School of Basic Medical Science, Xinxiang Medical University, Xinxiang, China
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9
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Zocchi M, Bartolini M, Maier JA, Castiglioni S. Low extracellular magnesium induces phenotypic and metabolic alterations in C2C12-derived myotubes. Sci Rep 2023; 13:19425. [PMID: 37940675 PMCID: PMC10632379 DOI: 10.1038/s41598-023-46543-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2023] [Accepted: 11/02/2023] [Indexed: 11/10/2023] Open
Abstract
Magnesium (Mg) has a pivotal role in upholding skeletal muscle health and optimizing performance. Its deficiency decreases muscle strength, and an association has been reported between Mg intake and sarcopenia. To gain a comprehensive understanding of the repercussions arising from low Mg concentrations on muscle behavior, we employed an in vitro model utilizing C2C12-derived myotubes. Myotubes cultured in low Mg show a significant reduction of thickness and a concomitant down-regulation of myosin heavy chain (MyHC), Myog and Myomixer. In parallel, myotubes shape their metabolism. Glycolysis is inhibited and beta-oxidation increases. These metabolic changes are consistent with the increase of MyHC I (slow) vs. MyHC II (fast) expression. We identified an essential player in these changes, namely nitric oxide (NO), as the increase in NO production appeared to orchestrate the observed modifications in myotube behavior and metabolism under low Mg conditions. Understanding these underlying mechanisms may pave the way for targeted interventions to ameliorate muscle-related conditions associated with Mg deficiency and contribute to enhancing overall muscle health and function.
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Affiliation(s)
- Monica Zocchi
- Department of Biomedical and Clinical Sciences, Università di Milano, 20157, Milano, Italy
| | - Marco Bartolini
- Department of Biomedical and Clinical Sciences, Università di Milano, 20157, Milano, Italy
| | - Jeanette A Maier
- Department of Biomedical and Clinical Sciences, Università di Milano, 20157, Milano, Italy
| | - Sara Castiglioni
- Department of Biomedical and Clinical Sciences, Università di Milano, 20157, Milano, Italy.
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10
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Hill MN, Haney M, Hillard CJ, Karhson DS, Vecchiarelli HA. The endocannabinoid system as a putative target for the development of novel drugs for the treatment of psychiatric illnesses. Psychol Med 2023; 53:7006-7024. [PMID: 37671673 PMCID: PMC10719691 DOI: 10.1017/s0033291723002465] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Revised: 07/25/2023] [Accepted: 07/28/2023] [Indexed: 09/07/2023]
Abstract
Cannabis is well established to impact affective states, emotion and perceptual processing, primarily through its interactions with the endocannabinoid system. While cannabis use is quite prevalent in many individuals afflicted with psychiatric illnesses, there is considerable controversy as to whether cannabis may worsen these conditions or provide some form of therapeutic benefit. The development of pharmacological agents which interact with components of the endocannabinoid system in more localized and discrete ways then via phytocannabinoids found in cannabis, has allowed the investigation if direct targeting of the endocannabinoid system itself may represent a novel approach to treat psychiatric illness without the potential untoward side effects associated with cannabis. Herein we review the current body of literature regarding the various pharmacological tools that have been developed to target the endocannabinoid system, their impact in preclinical models of psychiatric illness and the recent data emerging of their utilization in clinical trials for psychiatric illnesses, with a specific focus on substance use disorders, trauma-related disorders, and autism. We highlight several candidate drugs which target endocannabinoid function, particularly inhibitors of endocannabinoid metabolism or modulators of cannabinoid receptor signaling, which have emerged as potential candidates for the treatment of psychiatric conditions, particularly substance use disorder, anxiety and trauma-related disorders and autism spectrum disorders. Although there needs to be ongoing clinical work to establish the potential utility of endocannabinoid-based drugs for the treatment of psychiatric illnesses, the current data available is quite promising and shows indications of several potential candidate diseases which may benefit from this approach.
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Affiliation(s)
- Matthew N. Hill
- Departments of Cell Biology and Anatomy & Psychiatry, Cumming School of Medicine, Hotchkiss Brain Institute and The Mathison Centre for Mental Health Research and Education, University of Calgary, Calgary, Canada
| | - Margaret Haney
- Department of Psychiatry, New York State Psychiatric Institute and Columbia University Irving Medical Center, New York, USA
| | - Cecilia J. Hillard
- Department of Pharmacology and Toxicology, Neuroscience Research Center, Medical College of Wisconsin, Milwaukee, USA
| | - Debra S. Karhson
- Department of Psychology, University of New Orleans, New Orleans, USA
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11
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Richardson RS, Sulima A, Rice KC, Kucharczk JA, Janda KD, Nisbett KE, Koob GF, Vendruscolo LF, Leggio L. Pharmacological GHSR (ghrelin receptor) blockade reduces alcohol binge-like drinking in male and female mice. Neuropharmacology 2023; 238:109643. [PMID: 37369277 PMCID: PMC10513123 DOI: 10.1016/j.neuropharm.2023.109643] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2023] [Revised: 06/20/2023] [Accepted: 06/22/2023] [Indexed: 06/29/2023]
Abstract
Ghrelin is a peptide that is produced by endocrine cells that are primarily localized in the stomach. Ghrelin receptors (GHSR) are expressed in the brain and periphery. Preclinical and clinical studies support a role for ghrelin in alcohol drinking and seeking. The GHSR has been suggested to be a potential pharmacotherapeutic target for alcohol use disorder (AUD). However, the role of the ghrelin system and its potential modulation by biological sex on binge-like drinking has not been comprehensively investigated. The present study tested six GHSR antagonists in an alcohol binge-like drinking procedure in male and female mice. Systemic administration of the GHSR antagonists JMV2959, PF-5190457, PF-6870961, and HM-04 reduced alcohol intake in both male and female mice. YIL-781 decreased intake in males, and LEAP2 (likely peripherally restricted) did not reduce intake in mice of either sex. We also administered LEAP2 and JMV2959 intracerebroventricularly to investigate whether the effects of GHSR blockade on alcohol intake are mediated by central receptors. The central administration of LEAP2 and JMV2959 decreased alcohol intake, particularly in high-drinking animals. Finally, in a preliminary experiment, an anti-ghrelin vaccine was examined for its potential effect on binge-like drinking and had no effect. In all experiments, there was a lack of meaningful sex differences. These findings suggest that central GHSR mediates binge-like alcohol intake. These data reveal novel pharmacological compounds with translational potential in the treatment of AUD and provide further evidence of the GHSR as a potential treatment target for AUD.
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Affiliation(s)
- Rani S Richardson
- Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, Translational Addiction Medicine Branch, National Institute on Drug Abuse Intramural Research Program and National Institute on Alcohol Abuse and Alcoholism Division of Intramural Clinical and Biological Research, National Institutes of Health, Baltimore, MD, USA; Neurobiology of Addiction Section, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, Baltimore, MD, USA; Stress & Addiction Neuroscience Unit, National Institute on Drug Abuse Intramural Research Program and National Institute on Alcohol Abuse and Alcoholism Division of Intramural Clinical and Biological Research, National Institutes of Health, Baltimore, MD, USA; University of North Carolina School of Medicine MD/PhD Program, University of North Carolina, Chapel Hill, NC, USA; Department of Cell Biology and Physiology, University of North Carolina, Chapel Hill, NC, USA
| | - Agnieszka Sulima
- Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, Baltimore, MD, USA
| | - Kenner C Rice
- Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, Baltimore, MD, USA
| | - Jed A Kucharczk
- Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, Baltimore, MD, USA
| | - Kim D Janda
- Department of Chemistry, Department of Immunology and Microbial Science, The Skaggs Institute for Chemical Biology, WIRM Institute for Research and Medicine, The Scripps Research Institute, La Jolla, CA, USA
| | - Khalin E Nisbett
- Neurobiology of Addiction Section, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, Baltimore, MD, USA; Stress & Addiction Neuroscience Unit, National Institute on Drug Abuse Intramural Research Program and National Institute on Alcohol Abuse and Alcoholism Division of Intramural Clinical and Biological Research, National Institutes of Health, Baltimore, MD, USA; Graduate Program in Neuroscience, Graduate College, University of Illinois Chicago, Chicago, IL, USA
| | - George F Koob
- Neurobiology of Addiction Section, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, Baltimore, MD, USA
| | - Leandro F Vendruscolo
- Stress & Addiction Neuroscience Unit, National Institute on Drug Abuse Intramural Research Program and National Institute on Alcohol Abuse and Alcoholism Division of Intramural Clinical and Biological Research, National Institutes of Health, Baltimore, MD, USA.
| | - Lorenzo Leggio
- Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, Translational Addiction Medicine Branch, National Institute on Drug Abuse Intramural Research Program and National Institute on Alcohol Abuse and Alcoholism Division of Intramural Clinical and Biological Research, National Institutes of Health, Baltimore, MD, USA; Department of Behavioral and Social Sciences, Center for Alcohol and Addiction Studies, Brown University, Providence, RI, USA; Division of Addiction Medicine, Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD, USA; Department of Neuroscience, Georgetown University Medical Center, Washington, DC, USA.
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12
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Scrimieri R, Locatelli L, Cazzaniga A, Cazzola R, Malucelli E, Sorrentino A, Iotti S, Maier JA. Ultrastructural features mirror metabolic derangement in human endothelial cells exposed to high glucose. Sci Rep 2023; 13:15133. [PMID: 37704683 PMCID: PMC10499809 DOI: 10.1038/s41598-023-42333-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Accepted: 09/08/2023] [Indexed: 09/15/2023] Open
Abstract
High glucose-induced endothelial dysfunction is the early event that initiates diabetes-induced vascular disease. Here we employed Cryo Soft X-ray Tomography to obtain three-dimensional maps of high D-glucose-treated endothelial cells and their controls at nanometric spatial resolution. We then correlated ultrastructural differences with metabolic rewiring. While the total mitochondrial mass does not change, high D-glucose promotes mitochondrial fragmentation, as confirmed by the modulation of fission-fusion markers, and dysfunction, as demonstrated by the drop of membrane potential, the decreased oxygen consumption and the increased production of reactive oxygen species. The 3D ultrastructural analysis also indicates the accumulation of lipid droplets in cells cultured in high D-glucose. Indeed, because of the decrease of fatty acid β-oxidation induced by high D-glucose concentration, triglycerides are esterified into fatty acids and then stored into lipid droplets. We propose that the increase of lipid droplets represents an adaptive mechanism to cope with the overload of glucose and associated oxidative stress and metabolic dysregulation.
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Affiliation(s)
- Roberta Scrimieri
- Department of Biomedical and Clinical Sciences, Università degli Studi di Milano, 20157, Milan, Italy.
| | - Laura Locatelli
- Department of Biomedical and Clinical Sciences, Università degli Studi di Milano, 20157, Milan, Italy
| | - Alessandra Cazzaniga
- Department of Biomedical and Clinical Sciences, Università degli Studi di Milano, 20157, Milan, Italy
| | - Roberta Cazzola
- Department of Biomedical and Clinical Sciences, Università degli Studi di Milano, 20157, Milan, Italy
| | - Emil Malucelli
- Department of Pharmacy and Biotechnology, Università di Bologna, 40127, Bologna, Italy
| | - Andrea Sorrentino
- Mistral Beamline, ALBA Synchrotron Light Source, Cerdanyola del Valles, 08290, Barcelona, Spain
| | - Stefano Iotti
- Department of Pharmacy and Biotechnology, Università di Bologna, 40127, Bologna, Italy
- National Institute of Biostructures and Biosystems, Viale Delle Medaglie d'Oro 305, 00136, Rome, Italy
| | - Jeanette A Maier
- Department of Biomedical and Clinical Sciences, Università degli Studi di Milano, 20157, Milan, Italy.
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13
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Shahen-Zoabi S, Smoum R, Bingor A, Grad E, Nemirovski A, Shekh-Ahmad T, Mechoulam R, Yaka R. N-oleoyl glycine and N-oleoyl alanine attenuate alcohol self-administration and preference in mice. Transl Psychiatry 2023; 13:273. [PMID: 37524707 PMCID: PMC10390512 DOI: 10.1038/s41398-023-02574-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2023] [Revised: 07/19/2023] [Accepted: 07/25/2023] [Indexed: 08/02/2023] Open
Abstract
The endocannabinoid system (ECS) plays a key modulatory role during synaptic plasticity and homeostatic processes in the brain and has an important role in the neurobiological processes underlying drug addiction. We have previously shown that an elevated ECS response to psychostimulant (cocaine) is involved in regulating the development and expression of cocaine-conditioned reward and sensitization. We therefore hypothesized that drug-induced elevation in endocannabinoids (eCBs) and/or eCB-like molecules (eCB-Ls) may represent a protective mechanism against drug insult, and boosting their levels exogenously may strengthen their neuroprotective effects. Here, we determine the involvement of ECS in alcohol addiction. We first measured the eCBs and eCB-Ls levels in different brain reward system regions following chronic alcohol self-administration using LC-MS. We have found that following chronic intermittent alcohol consumption, N-oleoyl glycine (OlGly) levels were significantly elevated in the prefrontal cortex (PFC), and N-oleoyl alanine (OlAla) was significantly elevated in the PFC, nucleus accumbens (NAc) and ventral tegmental area (VTA) in a region-specific manner. We next tested whether exogenous administration of OlGly or OlAla would attenuate alcohol consumption and preference. We found that systemic administration of OlGly or OlAla (60 mg/kg, intraperitoneal) during intermittent alcohol consumption significantly reduced alcohol intake and preference without affecting the hedonic state. These findings suggest that the ECS negatively regulates alcohol consumption and boosting selective eCBs exogenously has beneficial effects against alcohol consumption and potentially in preventing relapse.
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Affiliation(s)
- Samah Shahen-Zoabi
- Institute for Drug Research (IDR), School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, 91120, Israel
| | - Reem Smoum
- Institute for Drug Research (IDR), School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, 91120, Israel
| | - Alexey Bingor
- Institute for Drug Research (IDR), School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, 91120, Israel
| | - Etty Grad
- Institute for Drug Research (IDR), School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, 91120, Israel
| | - Alina Nemirovski
- Institute for Drug Research (IDR), School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, 91120, Israel
| | - Tawfeeq Shekh-Ahmad
- Institute for Drug Research (IDR), School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, 91120, Israel
| | - Raphael Mechoulam
- Institute for Drug Research (IDR), School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, 91120, Israel
| | - Rami Yaka
- Institute for Drug Research (IDR), School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, 91120, Israel.
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14
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Mukhopadhyay B, Holovac K, Schuebel K, Mukhopadhyay P, Cinar R, Iyer S, Marietta C, Goldman D, Kunos G. The endocannabinoid system promotes hepatocyte progenitor cell proliferation and maturation by modulating cellular energetics. Cell Death Discov 2023; 9:104. [PMID: 36966147 PMCID: PMC10039889 DOI: 10.1038/s41420-023-01400-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2022] [Revised: 03/01/2023] [Accepted: 03/06/2023] [Indexed: 03/27/2023] Open
Abstract
The proliferation and differentiation of hepatic progenitor cells (HPCs) drive the homeostatic renewal of the liver under diverse conditions. Liver regeneration is associated with an increase in Axin2+Cnr1+ HPCs, along with a marked increase in the levels of the endocannabinoid anandamide (AEA). But the molecular mechanism linking AEA signaling to HPC proliferation and/or differentiation has not been explored. Here, we show that in vitro exposure of HPCs to AEA triggers both cell cycling and differentiation along with increased expression of Cnr1, Krt19, and Axin2. Mechanistically, we found that AEA promotes the nuclear localization of the transcription factor β-catenin, with subsequent induction of its downstream targets. Systemic analyses of cells after CRISPR-mediated knockout of the β-catenin-regulated transcriptome revealed that AEA modulates β-catenin-dependent cell cycling and differentiation, as well as interleukin pathways. Further, we found that AEA promotes OXPHOS in HPCs when amino acids and glucose are readily available as substrates, but AEA inhibits it when the cells rely primarily on fatty acid oxidation. Thus, the endocannabinoid system promotes hepatocyte renewal and maturation by stimulating the proliferation of Axin2+Cnr1+ HPCs via the β-catenin pathways while modulating the metabolic activity of their precursor cells.
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Affiliation(s)
- Bani Mukhopadhyay
- Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA.
- Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA.
| | - Kellie Holovac
- Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA
| | - Kornel Schuebel
- Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA
| | - Partha Mukhopadhyay
- Laboratory of Cardiovascular Physiology and Tissue Injury, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA
| | - Resat Cinar
- Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA
| | - Sindhu Iyer
- Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA
| | - Cheryl Marietta
- Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA
| | - David Goldman
- Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA
| | - George Kunos
- Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA
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15
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Jerlhag E. Animal studies reveal that the ghrelin pathway regulates alcohol-mediated responses. Front Psychiatry 2023; 14:1050973. [PMID: 36970276 PMCID: PMC10030715 DOI: 10.3389/fpsyt.2023.1050973] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Accepted: 02/21/2023] [Indexed: 03/29/2023] Open
Abstract
Alcohol use disorder (AUD) is often described as repeated phases of binge drinking, compulsive alcohol-taking, craving for alcohol during withdrawal, and drinking with an aim to a reduce the negative consequences. Although multifaceted, alcohol-induced reward is one aspect influencing the former three of these. The neurobiological mechanisms regulating AUD processes are complex and one of these systems is the gut-brain peptide ghrelin. The vast physiological properties of ghrelin are mediated via growth hormone secretagogue receptor (GHSR, ghrelin receptor). Ghrelin is well known for its ability to control feeding, hunger, and metabolism. Moreover, ghrelin signaling appears central for alcohol-mediated responses; findings reviewed herein. In male rodents GHSR antagonism reduces alcohol consumption, prevents relapse drinking, and attenuates the motivation to consume alcohol. On the other hand, ghrelin increases the consumption of alcohol. This ghrelin-alcohol interaction is also verified to some extent in humans with high alcohol consumption. In addition, either pharmacological or genetic suppression of GHSR decreases several alcohol-related effects (behavioral or neurochemical). Indeed, this suppression blocks the alcohol-induced hyperlocomotion and dopamine release in nucleus accumbens as well as ablates the alcohol reward in the conditioned place preference model. Although not fully elucidated, this interaction appears to involve areas central for reward, such as the ventral tegmental area (VTA) and brain nodes targeted by VTA projections. As reviewed briefly, the ghrelin pathway does not only modulate alcohol-mediated effects, it regulates reward-related behaviors induced by addictive drugs. Although personality traits like impulsivity and risk-taking behaviors are common in patients with AUD, the role of the ghrelin pathway thereof is unknown and remains to be studied. In summary, the ghrelin pathway regulates addiction processes like AUD and therefore the possibility that GHSR antagonism reduces alcohol or drug-taking should be explored in randomized clinical trials.
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16
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Kharbanda KK, Farokhnia M, Deschaine SL, Bhargava R, Rodriguez-Flores M, Casey CA, Goldstone AP, Jerlhag E, Leggio L, Rasineni K. Role of the ghrelin system in alcohol use disorder and alcohol-associated liver disease: A narrative review. Alcohol Clin Exp Res 2022; 46:2149-2159. [PMID: 36316764 PMCID: PMC9772086 DOI: 10.1111/acer.14967] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Revised: 10/21/2022] [Accepted: 10/28/2022] [Indexed: 11/07/2022]
Abstract
Unhealthy alcohol consumption is a global health problem. Adverse individual, public health, and socioeconomic consequences are attributable to harmful alcohol use. Epidemiological studies have shown that alcohol use disorder (AUD) and alcohol-associated liver disease (ALD) are the top two pathologies among alcohol-related diseases. Consistent with the major role that the liver plays in alcohol metabolism, uncontrolled drinking may cause significant damage to the liver. This damage is initiated by excessive fat accumulation in the liver, which can further progress to advanced liver disease. The only effective therapeutic strategies currently available for ALD are alcohol abstinence or liver transplantation. Any molecule with dual-pronged effects at the central and peripheral organs controlling addictive behaviors and associated metabolic pathways are a potentially important therapeutic target for treating AUD and ALD. Ghrelin, a hormone primarily derived from the stomach, has such properties, and regulates both behavioral and metabolic functions. In this review, we highlight recent advances in understanding the peripheral and central functions of the ghrelin system and its role in AUD and ALD pathogenesis. We first discuss the correlation between blood ghrelin concentrations and alcohol use or abstinence. Next, we discuss the role of ghrelin in alcohol-seeking behaviors and finally its role in the development of fatty liver by metabolic regulations and organ crosstalk. We propose that a better understanding of the ghrelin system could open an innovative avenue for improved treatments for AUD and associated medical consequences, including ALD.
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Affiliation(s)
- Kusum K. Kharbanda
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, Nebraska, USA
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska, USA
- Department of Biochemistry & Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska, USA
| | - Mehdi Farokhnia
- Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, Translational Addiction Medicine Branch, National Institute on Drug Abuse, Intramural Research Program and National Institute on Alcohol Abuse and Alcoholism, Division of Intramural Clinical and Biological Research, National Institutes of Health, Baltimore and Bethesda, Maryland, USA
- Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA
| | - Sara L. Deschaine
- Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, Translational Addiction Medicine Branch, National Institute on Drug Abuse, Intramural Research Program and National Institute on Alcohol Abuse and Alcoholism, Division of Intramural Clinical and Biological Research, National Institutes of Health, Baltimore and Bethesda, Maryland, USA
| | - Raghav Bhargava
- PsychoNeuroEndocrinology Research Group, Division of Psychiatry, Department of Brain Sciences, Imperial College London, Hammersmith Hospital, London, UK
| | - Marcela Rodriguez-Flores
- PsychoNeuroEndocrinology Research Group, Division of Psychiatry, Department of Brain Sciences, Imperial College London, Hammersmith Hospital, London, UK
| | - Carol A. Casey
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, Nebraska, USA
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska, USA
- Department of Biochemistry & Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska, USA
| | - Anthony P. Goldstone
- PsychoNeuroEndocrinology Research Group, Division of Psychiatry, Department of Brain Sciences, Imperial College London, Hammersmith Hospital, London, UK
| | - Elisabet Jerlhag
- Department of Pharmacology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
| | - Lorenzo Leggio
- Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, Translational Addiction Medicine Branch, National Institute on Drug Abuse, Intramural Research Program and National Institute on Alcohol Abuse and Alcoholism, Division of Intramural Clinical and Biological Research, National Institutes of Health, Baltimore and Bethesda, Maryland, USA
- Medication Development Program, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, Baltimore, Maryland, USA
- Center for Alcohol and Addiction Studies, Department of Behavioral and Social Sciences, Brown University, Providence, Rhode Island, USA
- Division of Addiction Medicine, Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA
- Department of Neuroscience, Georgetown University Medical Center, Washington DC, USA
| | - Karuna Rasineni
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, Nebraska, USA
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska, USA
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17
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Osna NA, Rasineni K, Ganesan M, Donohue TM, Kharbanda KK. Pathogenesis of Alcohol-Associated Liver Disease. J Clin Exp Hepatol 2022; 12:1492-1513. [PMID: 36340300 PMCID: PMC9630031 DOI: 10.1016/j.jceh.2022.05.004] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Accepted: 05/25/2022] [Indexed: 12/12/2022] Open
Abstract
Excessive alcohol consumption is a global healthcare problem with enormous social, economic, and clinical consequences. While chronic, heavy alcohol consumption causes structural damage and/or disrupts normal organ function in virtually every tissue of the body, the liver sustains the greatest damage. This is primarily because the liver is the first to see alcohol absorbed from the gastrointestinal tract via the portal circulation and second, because the liver is the principal site of ethanol metabolism. Alcohol-induced damage remains one of the most prevalent disorders of the liver and a leading cause of death or transplantation from liver disease. Despite extensive research on the pathophysiology of this disease, there are still no targeted therapies available. Given the multifactorial mechanisms for alcohol-associated liver disease pathogenesis, it is conceivable that a multitherapeutic regimen is needed to treat different stages in the spectrum of this disease.
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Key Words
- AA, Arachidonic acid
- ADH, Alcohol dehydrogenase
- AH, Alcoholic hepatitis
- ALD, Alcohol-associated liver disease
- ALDH, Aldehyde dehydrogenase
- ALT, Alanine transaminase
- ASH, Alcohol-associated steatohepatitis
- AST, Aspartate transaminase
- AUD, Alcohol use disorder
- BHMT, Betaine-homocysteine-methyltransferase
- CD, Cluster of differentiation
- COX, Cycloxygenase
- CTLs, Cytotoxic T-lymphocytes
- CYP, Cytochrome P450
- CYP2E1, Cytochrome P450 2E1
- Cu/Zn SOD, Copper/zinc superoxide dismutase
- DAMPs, Damage-associated molecular patterns
- DC, Dendritic cells
- EDN1, Endothelin 1
- ER, Endoplasmic reticulum
- ETOH, Ethanol
- EVs, Extracellular vesicles
- FABP4, Fatty acid-binding protein 4
- FAF2, Fas-associated factor family member 2
- FMT, Fecal microbiota transplant
- Fn14, Fibroblast growth factor-inducible 14
- GHS-R1a, Growth hormone secretagogue receptor type 1a
- GI, GOsteopontinastrointestinal tract
- GSH Px, Glutathione peroxidase
- GSSG Rdx, Glutathione reductase
- GST, Glutathione-S-transferase
- GWAS, Genome-wide association studies
- H2O2, Hydrogen peroxide
- HA, Hyaluronan
- HCC, Hepatocellular carcinoma
- HNE, 4-hydroxynonenal
- HPMA, 3-hydroxypropylmercapturic acid
- HSC, Hepatic stellate cells
- HSD17B13, 17 beta hydroxy steroid dehydrogenase 13
- HSP 90, Heat shock protein 90
- IFN, Interferon
- IL, Interleukin
- IRF3, Interferon regulatory factor 3
- JAK, Janus kinase
- KC, Kupffer cells
- LCN2, Lipocalin 2
- M-D, Mallory–Denk
- MAA, Malondialdehyde-acetaldehyde protein adducts
- MAT, Methionine adenosyltransferase
- MCP, Macrophage chemotactic protein
- MDA, Malondialdehyde
- MIF, Macrophage migration inhibitory factor
- Mn SOD, Manganese superoxide dismutase
- Mt, Mitochondrial
- NK, Natural killer
- NKT, Natural killer T-lymphocytes
- OPN, Osteopontin
- PAMP, Pathogen-associated molecular patterns
- PNPLA3, Patatin-like phospholipase domain containing 3
- PUFA, Polyunsaturated fatty acid
- RIG1, Retinoic acid inducible gene 1
- SAH, S-adenosylhomocysteine
- SAM, S-adenosylmethionine
- SCD, Stearoyl-CoA desaturase
- STAT, Signal transduction and activator of transcription
- TIMP1, Tissue inhibitor matrix metalloproteinase 1
- TLR, Toll-like receptor
- TNF, Tumor necrosis factor-α
- alcohol
- alcohol-associated liver disease
- ethanol metabolism
- liver
- miRNA, MicroRNA
- p90RSK, 90 kDa ribosomal S6 kinase
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Affiliation(s)
- Natalia A. Osna
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE, 68105, USA
- Department of Internal Medicine, Omaha, NE, 68198, USA
| | - Karuna Rasineni
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE, 68105, USA
- Department of Internal Medicine, Omaha, NE, 68198, USA
| | - Murali Ganesan
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE, 68105, USA
- Department of Internal Medicine, Omaha, NE, 68198, USA
| | - Terrence M. Donohue
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE, 68105, USA
- Department of Internal Medicine, Omaha, NE, 68198, USA
- Department of Biochemistry & Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Kusum K. Kharbanda
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE, 68105, USA
- Department of Internal Medicine, Omaha, NE, 68198, USA
- Department of Biochemistry & Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA
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18
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Berland C, Castel J, Terrasi R, Montalban E, Foppen E, Martin C, Muccioli GG, Luquet S, Gangarossa G. Identification of an endocannabinoid gut-brain vagal mechanism controlling food reward and energy homeostasis. Mol Psychiatry 2022; 27:2340-2354. [PMID: 35075269 DOI: 10.1038/s41380-021-01428-z] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2021] [Revised: 12/07/2021] [Accepted: 12/23/2021] [Indexed: 12/11/2022]
Abstract
The regulation of food intake, a sine qua non requirement for survival, thoroughly shapes feeding and energy balance by integrating both homeostatic and hedonic values of food. Unfortunately, the widespread access to palatable food has led to the development of feeding habits that are independent from metabolic needs. Among these, binge eating (BE) is characterized by uncontrolled voracious eating. While reward deficit seems to be a major contributor of BE, the physiological and molecular underpinnings of BE establishment remain elusive. Here, we combined a physiologically relevant BE mouse model with multiscale in vivo approaches to explore the functional connection between the gut-brain axis and the reward and homeostatic brain structures. Our results show that BE elicits compensatory adaptations requiring the gut-to-brain axis which, through the vagus nerve, relies on the permissive actions of peripheral endocannabinoids (eCBs) signaling. Selective inhibition of peripheral CB1 receptors resulted in a vagus-dependent increased hypothalamic activity, modified metabolic efficiency, and dampened activity of mesolimbic dopamine circuit, altogether leading to the suppression of palatable eating. We provide compelling evidence for a yet unappreciated physiological integrative mechanism by which variations of peripheral eCBs control the activity of the vagus nerve, thereby in turn gating the additive responses of both homeostatic and hedonic brain circuits which govern homeostatic and reward-driven feeding. In conclusion, we reveal that vagus-mediated eCBs/CB1R functions represent an interesting and innovative target to modulate energy balance and counteract food-reward disorders.
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Affiliation(s)
- Chloé Berland
- Université de Paris, CNRS, Unité de Biologie Fonctionnelle et Adaptative, F-75013, Paris, France
| | - Julien Castel
- Université de Paris, CNRS, Unité de Biologie Fonctionnelle et Adaptative, F-75013, Paris, France
| | - Romano Terrasi
- Bioanalysis and Pharmacology of Bioactive Lipids Research Group, Louvain Drug Research Institute, Université catholique de Louvain, 1200, Brussels, Belgium
| | - Enrica Montalban
- Université de Paris, CNRS, Unité de Biologie Fonctionnelle et Adaptative, F-75013, Paris, France
| | - Ewout Foppen
- Université de Paris, CNRS, Unité de Biologie Fonctionnelle et Adaptative, F-75013, Paris, France
| | - Claire Martin
- Université de Paris, CNRS, Unité de Biologie Fonctionnelle et Adaptative, F-75013, Paris, France
| | - Giulio G Muccioli
- Bioanalysis and Pharmacology of Bioactive Lipids Research Group, Louvain Drug Research Institute, Université catholique de Louvain, 1200, Brussels, Belgium
| | - Serge Luquet
- Université de Paris, CNRS, Unité de Biologie Fonctionnelle et Adaptative, F-75013, Paris, France
| | - Giuseppe Gangarossa
- Université de Paris, CNRS, Unité de Biologie Fonctionnelle et Adaptative, F-75013, Paris, France.
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19
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Bornscheuer L, Lundin A, Forsell Y, Lavebratt C, Melas PA. The cannabinoid receptor-1 gene interacts with stressful life events to increase the risk for problematic alcohol use. Sci Rep 2022; 12:4963. [PMID: 35322131 PMCID: PMC8941304 DOI: 10.1038/s41598-022-08980-w] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2021] [Accepted: 03/15/2022] [Indexed: 02/07/2023] Open
Abstract
Problematic alcohol use is a major contributor to the global burden of death and disabilities, and it represents a public health concern that has grown substantially following the COVID-19 pandemic. The available treatment options remain limited and to develop better pharmacotherapies for alcohol misuse we need to identify suitable biological targets. Previous research has implicated the brain’s endocannabinoid system (ECS) in psychiatric and stress-related outcomes, including substance use and habituation to repeated stress. Moreover, genetic variants in the cannabinoid-1 receptor gene (CNR1; CB1R) have been associated with personality traits, which are in turn predictors of substance use disorders. To date, however, no human genome-wide association study has provided evidence for an involvement of the ECS in substance use outcomes. One reason for this ECS-related “missing heritability” may be unexamined gene-environment interactions. To explore this possibility, we conducted cross-sectional analyses using DNA samples and stress-exposure data from a longitudinal Swedish population-based study (N = 2,915). Specifically, we genotyped rs2023239, a functional C/T single nucleotide polymorphism in CNR1, previously reported to be associated with CNR1 binding in the brain, subjective reward following alcohol intake, and alcohol cue-elicited brain activation. Our two outcomes of interest were (i) problematic alcohol use based on the Alcohol Use Disorders Identification Test (AUDIT), and (ii) personality trait scores based on the Five Factor Model. We found no baseline association between rs2023239 and problematic alcohol use or personality traits. However, there was a clear trend for interaction between rs2023239’s risk allele (C) and stressful life events (SLEs) in both childhood and adulthood, which predicted problematic alcohol use. Although not significant, there was also some indication that the risk allele interacted with child SLEs to increase scores on neuroticism. Our study supports the notion that the ECS can affect alcohol intake behaviors by interacting with life adversities and is—to the best of our knowledge—the first to focus on the interaction between CNR1 and stressors in both childhood and adulthood in humans. Further studies are warranted to confirm these findings.
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Affiliation(s)
- Lisa Bornscheuer
- Department of Public Health Sciences, Stockholm University, 10691, Stockholm, Sweden.,Center for Molecular Medicine, L8:00, Karolinska University Hospital, 17176, Stockholm, Sweden
| | - Andreas Lundin
- Department of Global Public Health, Karolinska Institutet, 17177, Stockholm, Sweden
| | - Yvonne Forsell
- Department of Global Public Health, Karolinska Institutet, 17177, Stockholm, Sweden
| | - Catharina Lavebratt
- Center for Molecular Medicine, L8:00, Karolinska University Hospital, 17176, Stockholm, Sweden.,Department of Molecular Medicine and Surgery, Karolinska Institutet, 17176, Stockholm, Sweden
| | - Philippe A Melas
- Center for Molecular Medicine, L8:00, Karolinska University Hospital, 17176, Stockholm, Sweden. .,Center for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet and Stockholm Health Care Services, 11364, Stockholm, Sweden.
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20
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Gupta S, Mukhopadhyay S, Mitra A. Therapeutic potential of GHSR-1A antagonism in alcohol dependence, a review. Life Sci 2022; 291:120316. [PMID: 35016882 DOI: 10.1016/j.lfs.2022.120316] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2021] [Revised: 01/05/2022] [Accepted: 01/05/2022] [Indexed: 11/28/2022]
Abstract
Growth hormone secretagogue receptor type 1A (GHSR-1A) is a functional receptor of orexigenic peptide ghrelin and is highly expressed in mesolimbic dopaminergic systems that regulate incentive value of artificial reward in substance abuse. Interestingly, GHSR-1A has also shown ligand-independent constitutive activity. Alcohol use disorder (AUD) is one of the growing concerns worldwide as it involves complex neuro-psycho-endocrinological interactions. Positive correlation of acylated ghrelin and alcohol-induced human brain response in the right and left ventral striatum are evident. In the last decade, the beneficial effects of ghrelin receptor (GHSR-1A) antagonism to suppress artificial reward circuitries and induce self-control for alcohol consumption have drawn significant attention from researchers. In this updated review, we summarize the available recent preclinical, clinical, and experimental data to discuss functional, molecular actions of central ghrelin-GHSR-1A signaling in different craving levels for alcohol as well as to promote "GHSR-1A antagonism" as one of the potential therapies in early abstinence.
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Affiliation(s)
- Shreyasi Gupta
- Department of Zoology, Triveni Devi Bhalotia College, Raniganj, Paschim Bardhaman 713 347, West Bengal, India
| | - Sanchari Mukhopadhyay
- Department of Psychiatry, National Institute of Mental Health and Neurosciences, Hombegowda Nagar, Bengaluru 560029, India
| | - Arkadeep Mitra
- Department of Zoology, City College, 102/1, Raja Rammohan Sarani, Kolkata 700 009, West Bengal, India.
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21
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Deschaine SL, Farokhnia M, Gregory-Flores A, Zallar LJ, You ZB, Sun H, Harvey DM, Marchette RCN, Tunstall BJ, Mani BK, Moose JE, Lee MR, Gardner E, Akhlaghi F, Roberto M, Hougland JL, Zigman JM, Koob GF, Vendruscolo LF, Leggio L. A closer look at alcohol-induced changes in the ghrelin system: novel insights from preclinical and clinical data. Addict Biol 2022; 27:e13033. [PMID: 33908131 PMCID: PMC8548413 DOI: 10.1111/adb.13033] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Revised: 01/16/2021] [Accepted: 03/06/2021] [Indexed: 02/06/2023]
Abstract
Ghrelin is a gastric-derived peptide hormone with demonstrated impact on alcohol intake and craving, but the reverse side of this bidirectional link, that is, the effects of alcohol on the ghrelin system, remains to be fully established. To further characterize this relationship, we examined (1) ghrelin levels via secondary analysis of human laboratory alcohol administration experiments with heavy-drinking participants; (2) expression of ghrelin, ghrelin receptor, and ghrelin-O-acyltransferase (GOAT) genes (GHRL, GHSR, and MBOAT4, respectively) in post-mortem brain tissue from individuals with alcohol use disorder (AUD) versus controls; (3) ghrelin levels in Ghsr knockout and wild-type rats following intraperitoneal (i.p.) alcohol administration; (4) effect of alcohol on ghrelin secretion from gastric mucosa cells ex vivo and GOAT enzymatic activity in vitro; and (5) ghrelin levels in rats following i.p. alcohol administration versus a calorically equivalent non-alcoholic sucrose solution. Acyl- and total-ghrelin levels decreased following acute alcohol administration in humans, but AUD was not associated with changes in central expression of ghrelin system genes in post-mortem tissue. In rats, alcohol decreased acyl-ghrelin, but not des-acyl-ghrelin, in both Ghsr knockout and wild-type rats. No dose-dependent effects of alcohol were observed on acyl-ghrelin secretion from gastric mucosa cells or on GOAT acylation activity. Lastly, alcohol and sucrose produced distinct effects on ghrelin in rats despite equivalent caloric value. Our findings suggest that alcohol acutely decreases peripheral ghrelin concentrations in vivo, but not in proportion to alcohol's caloric value or through direct interaction with ghrelin-secreting gastric mucosal cells, the ghrelin receptor, or the GOAT enzyme.
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Affiliation(s)
- Sara L. Deschaine
- Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, Translational Addiction Medicine Branch, National Institute on Drug Abuse and National, Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Baltimore, Maryland, USA
| | - Mehdi Farokhnia
- Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, Translational Addiction Medicine Branch, National Institute on Drug Abuse and National, Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Baltimore, Maryland, USA,Center on Compulsive Behaviors, National Institutes of Health, Bethesda, Maryland, USA,Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA
| | - Adriana Gregory-Flores
- Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, Translational Addiction Medicine Branch, National Institute on Drug Abuse and National, Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Baltimore, Maryland, USA,Neurobiology of Addiction Section, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland, USA
| | - Lia J. Zallar
- Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, Translational Addiction Medicine Branch, National Institute on Drug Abuse and National, Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Baltimore, Maryland, USA,Neurobiology of Addiction Section, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland, USA
| | - Zhi-Bing You
- Neuropsychopharmacology Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland, USA
| | - Hui Sun
- Clinical Core Laboratory, Office of the Clinical Director, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA
| | - Deon M. Harvey
- Office of the Scientific Director, National Institute on Drug Abuse, Baltimore, Maryland, USA
| | - Renata C. N. Marchette
- Center on Compulsive Behaviors, National Institutes of Health, Bethesda, Maryland, USA,Neurobiology of Addiction Section, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland, USA
| | - Brendan J. Tunstall
- Neurobiology of Addiction Section, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland, USA
| | - Bharath K. Mani
- Center for Hypothalamic Research, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas, USA
| | - Jacob E. Moose
- Syracuse Biomaterials Institute, Syracuse University, Syracuse, New York, USA,Department of Chemistry, Syracuse University, Syracuse, New York, USA
| | - Mary R. Lee
- Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, Translational Addiction Medicine Branch, National Institute on Drug Abuse and National, Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Baltimore, Maryland, USA
| | - Eliot Gardner
- Neuropsychopharmacology Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland, USA
| | - Fatemeh Akhlaghi
- Clinical Pharmacokinetics Research Laboratory, Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, Rhode Island, USA
| | - Marisa Roberto
- Department of Neuroscience, The Scripps Research Institute, La Jolla, California, USA
| | - James L. Hougland
- Syracuse Biomaterials Institute, Syracuse University, Syracuse, New York, USA,Department of Chemistry, Syracuse University, Syracuse, New York, USA,BioInspired Syracuse, Syracuse University, Syracuse, New York, USA
| | - Jeffrey M. Zigman
- Center for Hypothalamic Research, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas, USA,Division of Endocrinology, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas, USA,Department of Psychiatry, UT Southwestern Medical Center, Dallas, Texas, USA
| | - George F. Koob
- Neurobiology of Addiction Section, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland, USA
| | - Leandro F. Vendruscolo
- Neurobiology of Addiction Section, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland, USA
| | - Lorenzo Leggio
- Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, Translational Addiction Medicine Branch, National Institute on Drug Abuse and National, Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Baltimore, Maryland, USA,Center on Compulsive Behaviors, National Institutes of Health, Bethesda, Maryland, USA,Medication Development Program, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, Baltimore, Maryland, USA,Center for Alcohol and Addiction Studies, Department of Behavioral and Social Sciences, School of Public Health, Brown University, Providence, Rhode Island, USA,Division of Addiction Medicine, Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA,Department of Neuroscience, Georgetown University Medical Center, Washington, District of Columbia, USA
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22
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Deschaine SL, Leggio L. From "Hunger Hormone" to "It's Complicated": Ghrelin Beyond Feeding Control. Physiology (Bethesda) 2022; 37:5-15. [PMID: 34964687 PMCID: PMC8742734 DOI: 10.1152/physiol.00024.2021] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
Discovered as a peptide involved in releasing growth hormone, ghrelin was initially characterized as the "hunger hormone." However, emerging research indicates that ghrelin appears to play an important part in relaying information regarding nutrient availability and value and adjusting physiological and motivational processes accordingly. These functions make ghrelin an interesting therapeutic candidate for metabolic and neuropsychiatric diseases involving disrupted nutrition that can further potentiate the rewarding effect of maladaptive behaviors.
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Affiliation(s)
- Sara L. Deschaine
- 1Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, Translational Addiction Medicine Branch, National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Baltimore and Bethesda, Maryland
| | - Lorenzo Leggio
- 1Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, Translational Addiction Medicine Branch, National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Baltimore and Bethesda, Maryland,2Medication Development Program, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, Baltimore, Maryland,3Center for Alcohol and Addiction Studies, Department of Behavioral and Social Sciences, School of Public Health, Brown University, Providence, Rhode Island,4Division of Addiction Medicine, Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, Maryland,5Department of Neuroscience, Georgetown University Medical Center, Washington, District of Columbia
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23
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Shen M, Manca C, Suriano F, Nallabelli N, Pechereau F, Allam-Ndoul B, Iannotti FA, Flamand N, Veilleux A, Cani PD, Silvestri C, Di Marzo V. Three of a Kind: Control of the Expression of Liver-Expressed Antimicrobial Peptide 2 (LEAP2) by the Endocannabinoidome and the Gut Microbiome. MOLECULES (BASEL, SWITZERLAND) 2021; 27:molecules27010001. [PMID: 35011234 PMCID: PMC8746324 DOI: 10.3390/molecules27010001] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/30/2021] [Revised: 12/16/2021] [Accepted: 12/16/2021] [Indexed: 02/07/2023]
Abstract
The endocannabinoidome (expanded endocannabinoid system, eCBome)-gut microbiome (mBIome) axis plays a fundamental role in the control of energy intake and processing. The liver-expressed antimicrobial peptide 2 (LEAP2) is a recently identified molecule acting as an antagonist of the ghrelin receptor and hence a potential effector of energy metabolism, also at the level of the gastrointestinal system. Here we investigated the role of the eCBome-gut mBIome axis in the control of the expression of LEAP2 in the liver and, particularly, the intestine. We confirm that the small intestine is a strong contributor to the circulating levels of LEAP2 in mice, and show that: (1) intestinal Leap2 expression is profoundly altered in the liver and small intestine of 13 week-old germ-free (GF) male mice, which also exhibit strong alterations in eCBome signaling; fecal microbiota transfer (FMT) from conventionally raised to GF mice completely restored normal Leap2 expression after 7 days from this procedure; in 13 week-old female GF mice no significant change was observed; (2) Leap2 expression in organoids prepared from the mouse duodenum is elevated by the endocannabinoid noladin ether, whereas in human Caco-2/15 epithelial intestinal cells it is elevated by PPARγ activation by rosiglitazone; (3) Leap2 expression is elevated in the ileum of mice with either high-fat diet—or genetic leptin signaling deficiency—(i.e., ob/ob and db/db mice) induced obesity. Based on these results, we propose that LEAP2 originating from the small intestine may represent a player in eCBome- and/or gut mBIome-mediated effects on food intake and energy metabolism.
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Affiliation(s)
- Mélissa Shen
- Quebec Heart and Lung Institute Research Centre, Department of Medicine, Faculty of Medicine, Université Laval, Quebec City, QC G1V 0A6, Canada; (M.S.); (C.M.); (N.N.); (N.F.)
| | - Claudia Manca
- Quebec Heart and Lung Institute Research Centre, Department of Medicine, Faculty of Medicine, Université Laval, Quebec City, QC G1V 0A6, Canada; (M.S.); (C.M.); (N.N.); (N.F.)
- Unité Mixte Internationale en Recherche Chimique et Biomoléculaire du Microbiome et son Impact sur la Santé Métabolique et la Nutrition, Université Laval, Quebec City, QC G1V 0A6, Canada
| | - Francesco Suriano
- Metabolism and Nutrition Research Group, Louvain Drug Research Institute (LDRI), Walloon Excellence in Life Sciences and BIOtechnology (WELBIO), UCLouvain, Université Catholique de Louvain, 1200 Brussels, Belgium; (F.S.); (P.D.C.)
| | - Nayudu Nallabelli
- Quebec Heart and Lung Institute Research Centre, Department of Medicine, Faculty of Medicine, Université Laval, Quebec City, QC G1V 0A6, Canada; (M.S.); (C.M.); (N.N.); (N.F.)
| | - Florent Pechereau
- Centre Nutrition, Santé et Société (NUTRISS), Institut sur la Nutrition et les Aliments Fonctionnels (INAF), École de Nutrition (FSAA), Université Laval, Quebec City, QC G1V 0A6, Canada; (F.P.); (B.A.-N.); (A.V.)
| | - Bénédicte Allam-Ndoul
- Centre Nutrition, Santé et Société (NUTRISS), Institut sur la Nutrition et les Aliments Fonctionnels (INAF), École de Nutrition (FSAA), Université Laval, Quebec City, QC G1V 0A6, Canada; (F.P.); (B.A.-N.); (A.V.)
| | - Fabio Arturo Iannotti
- Endocannabinoid Research Group, Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, 80078 Pozzuoli, Italy;
| | - Nicolas Flamand
- Quebec Heart and Lung Institute Research Centre, Department of Medicine, Faculty of Medicine, Université Laval, Quebec City, QC G1V 0A6, Canada; (M.S.); (C.M.); (N.N.); (N.F.)
| | - Alain Veilleux
- Centre Nutrition, Santé et Société (NUTRISS), Institut sur la Nutrition et les Aliments Fonctionnels (INAF), École de Nutrition (FSAA), Université Laval, Quebec City, QC G1V 0A6, Canada; (F.P.); (B.A.-N.); (A.V.)
| | - Patrice D. Cani
- Metabolism and Nutrition Research Group, Louvain Drug Research Institute (LDRI), Walloon Excellence in Life Sciences and BIOtechnology (WELBIO), UCLouvain, Université Catholique de Louvain, 1200 Brussels, Belgium; (F.S.); (P.D.C.)
| | - Cristoforo Silvestri
- Quebec Heart and Lung Institute Research Centre, Department of Medicine, Faculty of Medicine, Université Laval, Quebec City, QC G1V 0A6, Canada; (M.S.); (C.M.); (N.N.); (N.F.)
- Centre Nutrition, Santé et Société (NUTRISS), Institut sur la Nutrition et les Aliments Fonctionnels (INAF), École de Nutrition (FSAA), Université Laval, Quebec City, QC G1V 0A6, Canada; (F.P.); (B.A.-N.); (A.V.)
- Correspondence: (C.S.); (V.D.); Tel.: +1-418-656-8711 (ext. 7229) (C.S.); +1-418-656-8711 (ext. 7263) (V.D.)
| | - Vincenzo Di Marzo
- Quebec Heart and Lung Institute Research Centre, Department of Medicine, Faculty of Medicine, Université Laval, Quebec City, QC G1V 0A6, Canada; (M.S.); (C.M.); (N.N.); (N.F.)
- Unité Mixte Internationale en Recherche Chimique et Biomoléculaire du Microbiome et son Impact sur la Santé Métabolique et la Nutrition, Université Laval, Quebec City, QC G1V 0A6, Canada
- Centre Nutrition, Santé et Société (NUTRISS), Institut sur la Nutrition et les Aliments Fonctionnels (INAF), École de Nutrition (FSAA), Université Laval, Quebec City, QC G1V 0A6, Canada; (F.P.); (B.A.-N.); (A.V.)
- Endocannabinoid Research Group, Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, 80078 Pozzuoli, Italy;
- Canada Excellence Research Chair on the Microbiome-Endocannabinoidome Axis in Metabolic Health, Université Laval, Quebec City, QC G1V 0A6, Canada
- Correspondence: (C.S.); (V.D.); Tel.: +1-418-656-8711 (ext. 7229) (C.S.); +1-418-656-8711 (ext. 7263) (V.D.)
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24
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Scholz O, Otter S, Welters A, Wörmeyer L, Dolenšek J, Klemen MS, Pohorec V, Eberhard D, Mrugala J, Hamacher A, Koch A, Sanz M, Hoffmann T, Hogeback J, Herebian D, Klöcker N, Piechot A, Mayatepek E, Meissner T, Stožer A, Lammert E. Peripherally active dextromethorphan derivatives lower blood glucose levels by targeting pancreatic islets. Cell Chem Biol 2021; 28:1474-1488.e7. [PMID: 34118188 DOI: 10.1016/j.chembiol.2021.05.011] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2020] [Revised: 03/09/2021] [Accepted: 05/17/2021] [Indexed: 12/12/2022]
Abstract
Dextromethorphan (DXM) acts as cough suppressant via its central action. Cell-protective effects of this drug have been reported in peripheral tissues, making DXM potentially useful for treatment of several common human diseases, such as type 2 diabetes mellitus (T2DM). Pancreatic islets are among the peripheral tissues that positively respond to DXM, and anti-diabetic effects of DXM were observed in two placebo-controlled, randomized clinical trials in humans with T2DM. Since these effects were associated with central side effects, we here developed chemical derivatives of DXM that pass the blood-brain barrier to a significantly lower extent than the original drug. We show that basic nitrogen-containing residues block central adverse events of DXM without reducing its anti-diabetic effects, including the protection of human pancreatic islets from cell death. These results show how to chemically modify DXM, and possibly other morphinans, as to exclude central side effects, while targeting peripheral tissues, such as pancreatic islets.
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Affiliation(s)
- Okka Scholz
- Institute for Vascular and Islet Cell Biology, German Diabetes Center (DDZ), Leibniz Center for Diabetes Research at Heinrich Heine University, 40225 Düsseldorf, Germany; Institute of Metabolic Physiology, Heinrich Heine University, 40225 Düsseldorf, Germany; Center of Competence for Innovative Diabetes Therapy (KomIT), German Diabetes Center (DDZ), 40225 Düsseldorf, Germany; German Center for Diabetes Research (DZD e.V.), Helmholtz Zentrum München, 85764 Neuherberg, Germany
| | - Silke Otter
- Institute for Vascular and Islet Cell Biology, German Diabetes Center (DDZ), Leibniz Center for Diabetes Research at Heinrich Heine University, 40225 Düsseldorf, Germany; Institute of Metabolic Physiology, Heinrich Heine University, 40225 Düsseldorf, Germany; Center of Competence for Innovative Diabetes Therapy (KomIT), German Diabetes Center (DDZ), 40225 Düsseldorf, Germany
| | - Alena Welters
- Institute of Metabolic Physiology, Heinrich Heine University, 40225 Düsseldorf, Germany; Department of General Pediatrics, Neonatology and Pediatric Cardiology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University, 40225 Düsseldorf, Germany
| | - Laura Wörmeyer
- Institute of Metabolic Physiology, Heinrich Heine University, 40225 Düsseldorf, Germany; Department of General Pediatrics, Neonatology and Pediatric Cardiology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University, 40225 Düsseldorf, Germany
| | - Jurij Dolenšek
- Faculty of Medicine, University of Maribor, Taborska ulica 8, 2000 Maribor, Slovenia; Faculty of Natural Sciences and Mathematics, University of Maribor, Koroška cesta 160, 2000 Maribor, Slovenia
| | - Maša Skelin Klemen
- Faculty of Medicine, University of Maribor, Taborska ulica 8, 2000 Maribor, Slovenia
| | - Viljem Pohorec
- Faculty of Medicine, University of Maribor, Taborska ulica 8, 2000 Maribor, Slovenia
| | - Daniel Eberhard
- Institute for Vascular and Islet Cell Biology, German Diabetes Center (DDZ), Leibniz Center for Diabetes Research at Heinrich Heine University, 40225 Düsseldorf, Germany; Institute of Metabolic Physiology, Heinrich Heine University, 40225 Düsseldorf, Germany
| | - Jessica Mrugala
- Institute for Vascular and Islet Cell Biology, German Diabetes Center (DDZ), Leibniz Center for Diabetes Research at Heinrich Heine University, 40225 Düsseldorf, Germany; Institute of Metabolic Physiology, Heinrich Heine University, 40225 Düsseldorf, Germany; German Center for Diabetes Research (DZD e.V.), Helmholtz Zentrum München, 85764 Neuherberg, Germany
| | - Anna Hamacher
- Institute for Vascular and Islet Cell Biology, German Diabetes Center (DDZ), Leibniz Center for Diabetes Research at Heinrich Heine University, 40225 Düsseldorf, Germany; Institute of Metabolic Physiology, Heinrich Heine University, 40225 Düsseldorf, Germany
| | - Angela Koch
- Institute of Neuro- and Sensory Physiology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University, 40225 Düsseldorf, Germany
| | - Miguel Sanz
- Center of Competence for Innovative Diabetes Therapy (KomIT), German Diabetes Center (DDZ), 40225 Düsseldorf, Germany; Taros Chemicals GmbH & Co. KG, 44227 Dortmund, Germany
| | - Torsten Hoffmann
- Center of Competence for Innovative Diabetes Therapy (KomIT), German Diabetes Center (DDZ), 40225 Düsseldorf, Germany; Taros Chemicals GmbH & Co. KG, 44227 Dortmund, Germany
| | - Jens Hogeback
- A&M Labor für Analytik und Metabolismusforschung Service GmbH, 50126 Bergheim, Germany
| | - Diran Herebian
- Department of General Pediatrics, Neonatology and Pediatric Cardiology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University, 40225 Düsseldorf, Germany
| | - Nikolaj Klöcker
- Institute of Neuro- and Sensory Physiology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University, 40225 Düsseldorf, Germany
| | - Alexander Piechot
- Center of Competence for Innovative Diabetes Therapy (KomIT), German Diabetes Center (DDZ), 40225 Düsseldorf, Germany; Taros Chemicals GmbH & Co. KG, 44227 Dortmund, Germany
| | - Ertan Mayatepek
- Department of General Pediatrics, Neonatology and Pediatric Cardiology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University, 40225 Düsseldorf, Germany
| | - Thomas Meissner
- Department of General Pediatrics, Neonatology and Pediatric Cardiology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University, 40225 Düsseldorf, Germany
| | - Andraž Stožer
- Faculty of Medicine, University of Maribor, Taborska ulica 8, 2000 Maribor, Slovenia
| | - Eckhard Lammert
- Institute for Vascular and Islet Cell Biology, German Diabetes Center (DDZ), Leibniz Center for Diabetes Research at Heinrich Heine University, 40225 Düsseldorf, Germany; Institute of Metabolic Physiology, Heinrich Heine University, 40225 Düsseldorf, Germany; Center of Competence for Innovative Diabetes Therapy (KomIT), German Diabetes Center (DDZ), 40225 Düsseldorf, Germany; German Center for Diabetes Research (DZD e.V.), Helmholtz Zentrum München, 85764 Neuherberg, Germany.
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The Peripheral Cannabinoid Receptor Type 1 (CB 1) as a Molecular Target for Modulating Body Weight in Man. Molecules 2021; 26:molecules26206178. [PMID: 34684760 PMCID: PMC8538448 DOI: 10.3390/molecules26206178] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2021] [Revised: 10/06/2021] [Accepted: 10/09/2021] [Indexed: 01/14/2023] Open
Abstract
The cannabinoid 1 (CB1) receptor regulates appetite and body weight; however, unwanted central side effects of both agonists (in wasting disorders) or antagonists (in obesity and diabetes) have limited their therapeutic utility. At the peripheral level, CB1 receptor activation impacts the energy balance of mammals in a number of different ways: inhibiting satiety and emesis, increasing food intake, altering adipokine and satiety hormone levels, altering taste sensation, decreasing lipolysis (fat break down), and increasing lipogenesis (fat generation). The CB1 receptor also plays an important role in the gut–brain axis control of appetite and satiety. The combined effect of peripheral CB1 activation is to promote appetite, energy storage, and energy preservation (and the opposite is true for CB1 antagonists). Therefore, the next generation of CB1 receptor medicines (agonists and antagonists, and indirect modulators of the endocannabinoid system) have been peripherally restricted to mitigate these issues, and some of these are already in clinical stage development. These compounds also have demonstrated potential in other conditions such as alcoholic steatohepatitis and diabetic nephropathy (peripherally restricted CB1 antagonists) and pain conditions (peripherally restricted CB1 agonists and FAAH inhibitors). This review will discuss the mechanisms by which peripheral CB1 receptors regulate body weight, and the therapeutic utility of peripherally restricted drugs in the management of body weight and beyond.
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Santos-Molina L, Herrerias A, Zawatsky CN, Gunduz-Cinar O, Cinar R, Iyer MR, Wood CM, Lin Y, Gao B, Kunos G, Godlewski G. Effects of a Peripherally Restricted Hybrid Inhibitor of CB1 Receptors and iNOS on Alcohol Drinking Behavior and Alcohol-Induced Endotoxemia. Molecules 2021; 26:5089. [PMID: 34443679 PMCID: PMC8399901 DOI: 10.3390/molecules26165089] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Revised: 08/17/2021] [Accepted: 08/19/2021] [Indexed: 12/26/2022] Open
Abstract
Alcohol consumption is associated with gut dysbiosis, increased intestinal permeability, endotoxemia, and a cascade that leads to persistent systemic inflammation, alcoholic liver disease, and other ailments. Craving for alcohol and its consequences depends, among other things, on the endocannabinoid system. We have analyzed the relative role of central vs. peripheral cannabinoid CB1 receptors (CB1R) using a "two-bottle" as well as a "drinking in the dark" paradigm in mice. The globally acting CB1R antagonist rimonabant and the non-brain penetrant CB1R antagonist JD5037 inhibited voluntary alcohol intake upon systemic but not upon intracerebroventricular administration in doses that elicited anxiogenic-like behavior and blocked CB1R-induced hypothermia and catalepsy. The peripherally restricted hybrid CB1R antagonist/iNOS inhibitor S-MRI-1867 was also effective in reducing alcohol consumption after oral gavage, while its R enantiomer (CB1R inactive/iNOS inhibitor) was not. The two MRI-1867 enantiomers were equally effective in inhibiting an alcohol-induced increase in portal blood endotoxin concentration that was caused by increased gut permeability. We conclude that (i) activation of peripheral CB1R plays a dominant role in promoting alcohol intake and (ii) the iNOS inhibitory function of MRI-1867 helps in mitigating the alcohol-induced increase in endotoxemia.
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Affiliation(s)
- Luis Santos-Molina
- Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA; (L.S.-M.); (A.H.); (G.K.)
| | - Alexa Herrerias
- Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA; (L.S.-M.); (A.H.); (G.K.)
| | - Charles N. Zawatsky
- Section on Fibrotic Disorders, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA; (C.N.Z.); (R.C.)
| | - Ozge Gunduz-Cinar
- Laboratory of Behavioral and Genomic Neuroscience, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA;
| | - Resat Cinar
- Section on Fibrotic Disorders, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA; (C.N.Z.); (R.C.)
| | - Malliga R. Iyer
- Section on Medicinal Chemistry, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA; (M.R.I.); (C.M.W.)
| | - Casey M. Wood
- Section on Medicinal Chemistry, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA; (M.R.I.); (C.M.W.)
| | - Yuhong Lin
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA; (Y.L.); (B.G.)
| | - Bin Gao
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA; (Y.L.); (B.G.)
| | - George Kunos
- Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA; (L.S.-M.); (A.H.); (G.K.)
| | - Grzegorz Godlewski
- Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA; (L.S.-M.); (A.H.); (G.K.)
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27
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Lee JY, Lee GJ, Nakamura A, Lee PR, Kim Y, Won CH, Furue H, Oh SB. Involvement of cannabinoid type 1 receptor in fasting-induced analgesia. Mol Pain 2021; 16:1744806920969476. [PMID: 33121353 PMCID: PMC7607739 DOI: 10.1177/1744806920969476] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023] Open
Abstract
The endocannabinoid system (ECS) is known to modulate not only food intake but also pain, especially via the cannabinoid type 1 receptor (CB1R) expressed throughout the central nervous system and the peripheral tissues. Our previous study demonstrated that fasting produces an analgesic effect in adult male mice, which is reversed by intraperitoneal (i.p.) administration of CB1R antagonist (SR 141716). In the present study, we further examined the effect of CB1R expressed in the peripheral tissues. In the formalin-induced inflammatory pain model, i.p. administration of peripherally restricted CB1R antagonist (AM 6545) reversed fasting-induced analgesia. However, intraplantar administration of SR 141716 did not affect fasting-induced analgesia. Furthermore, mRNA expression of CB1R did not change in the formalin model by fasting in the dorsal root ganglia. The formalin-induced c-Fos expression at the spinal cord level was not affected by fasting, and in vivo recording from the superficial dorsal horn of the lumbar spinal cord revealed that fasting did not affect formalin-induced neural activity, which indicates minimal involvement of the spinal cord in fasting-induced analgesia. Finally, when we performed subdiaphragmatic vagotomy to block the hunger signal from the gastrointestinal (GI) system, AM 6545 did not affect fasting-induced analgesia, but SR 141716 still reversed fasting-induced analgesia. Taken together, our results suggest that both peripheral and central CB1Rs contribute to fasting-induced analgesic effects and the CB1Rs in the GI system which transmit fasting signals to the brain, rather than those in the peripheral sensory neurons, may contribute to fasting-induced analgesic effects.
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Affiliation(s)
- Jeong-Yun Lee
- Department of Brain and Cognitive Sciences, College of Natural Sciences, Seoul National University, Seoul, Republic of Korea
| | - Grace J Lee
- Department of Brain and Cognitive Sciences, College of Natural Sciences, Seoul National University, Seoul, Republic of Korea
| | - Ayumi Nakamura
- Department of Neurophysiology, Hyogo College of Medicine, Nishinomiya, Japan
| | - Pa Reum Lee
- Department of Brain and Cognitive Sciences, College of Natural Sciences, Seoul National University, Seoul, Republic of Korea
| | - Yeajin Kim
- Department of Brain and Cognitive Sciences, College of Natural Sciences, Seoul National University, Seoul, Republic of Korea
| | - Chan Hee Won
- Department of Neurobiology and Physiology, Dental Research Institute, School of Dentistry, Seoul National University, Seoul, Republic of Korea
| | - Hidemasa Furue
- Department of Neurophysiology, Hyogo College of Medicine, Nishinomiya, Japan
| | - Seog Bae Oh
- Department of Brain and Cognitive Sciences, College of Natural Sciences, Seoul National University, Seoul, Republic of Korea.,Department of Neurobiology and Physiology, Dental Research Institute, School of Dentistry, Seoul National University, Seoul, Republic of Korea
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Cinar R, Park JK, Zawatsky CN, Coffey NJ, Bodine SP, Abdalla J, Yokoyama T, Jourdan T, Jay L, Zuo MXG, O'Brien KJ, Huang J, Mackie K, Alimardanov A, Iyer MR, Gahl WA, Kunos G, Gochuico BR, Malicdan MCV. CB 1 R and iNOS are distinct players promoting pulmonary fibrosis in Hermansky-Pudlak syndrome. Clin Transl Med 2021; 11:e471. [PMID: 34323400 PMCID: PMC8255071 DOI: 10.1002/ctm2.471] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2021] [Revised: 06/02/2021] [Accepted: 06/07/2021] [Indexed: 02/06/2023] Open
Abstract
Hermansky-Pudlak syndrome (HPS) is a rare genetic disorder which, in its most common and severe form, HPS-1, leads to fatal adult-onset pulmonary fibrosis (PF) with no effective treatment. We evaluated the role of the endocannabinoid/CB1 R system and inducible nitric oxide synthase (iNOS) for dual-target therapeutic strategy using human bronchoalveolar lavage fluid (BALF), lung samples from patients with HPS and controls, HPS-PF patient-derived lung fibroblasts, and bleomycin-induced PF in pale ear mice (HPS1ep/ep ). We found overexpression of CB1 R and iNOS in fibrotic lungs of HPSPF patients and bleomycin-infused pale ear mice. The endocannabinoid anandamide was elevated in BALF and negatively correlated with pulmonary function parameters in HPSPF patients and pale ear mice with bleomycin-induced PF. Simultaneous targeting of CB1 R and iNOS by MRI-1867 yielded greater antifibrotic efficacy than inhibiting either target alone by attenuating critical pathologic pathways. Moreover, MRI-1867 treatment abrogated bleomycin-induced increases in lung levels of the profibrotic interleukin-11 via iNOS inhibition and reversed mitochondrial dysfunction via CB1 R inhibition. Dual inhibition of CB1 R and iNOS is an effective antifibrotic strategy for HPSPF.
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Affiliation(s)
- Resat Cinar
- Section on Fibrotic DisordersNational Institute on Alcohol Abuse and Alcoholism, National Institutes of HealthMarylandUSA
- Laboratory of Physiologic StudiesNational Institute on Alcohol Abuse and AlcoholismNational Institutes of HealthRockvilleMarylandUSA
| | - Joshua K. Park
- Laboratory of Physiologic StudiesNational Institute on Alcohol Abuse and AlcoholismNational Institutes of HealthRockvilleMarylandUSA
| | - Charles N. Zawatsky
- Laboratory of Physiologic StudiesNational Institute on Alcohol Abuse and AlcoholismNational Institutes of HealthRockvilleMarylandUSA
| | - Nathan J. Coffey
- Laboratory of Physiologic StudiesNational Institute on Alcohol Abuse and AlcoholismNational Institutes of HealthRockvilleMarylandUSA
| | - Steven P. Bodine
- Section of Human Biochemical GeneticsMedical Genetics BranchNational Human Genome Research InstituteNational Institutes of HealthBethesdaMarylandUSA
| | - Jasmina Abdalla
- Laboratory of Physiologic StudiesNational Institute on Alcohol Abuse and AlcoholismNational Institutes of HealthRockvilleMarylandUSA
| | - Tadafumi Yokoyama
- Section of Human Biochemical GeneticsMedical Genetics BranchNational Human Genome Research InstituteNational Institutes of HealthBethesdaMarylandUSA
- Present address:
Department of PediatricsKanazawa UniversityKanazawaJapan
| | - Tony Jourdan
- Laboratory of Physiologic StudiesNational Institute on Alcohol Abuse and AlcoholismNational Institutes of HealthRockvilleMarylandUSA
- Present address:
INSERM Lipids, Nutrition, Cancer UMR1231University of Burgundy and Franche‐ComtéDijonFrance
| | - Lindsey Jay
- Laboratory of Physiologic StudiesNational Institute on Alcohol Abuse and AlcoholismNational Institutes of HealthRockvilleMarylandUSA
| | - Mei Xing G. Zuo
- Laboratory of Physiologic StudiesNational Institute on Alcohol Abuse and AlcoholismNational Institutes of HealthRockvilleMarylandUSA
| | - Kevin J. O'Brien
- Section of Human Biochemical GeneticsMedical Genetics BranchNational Human Genome Research InstituteNational Institutes of HealthBethesdaMarylandUSA
| | - Junfeng Huang
- Therapeutics Development BranchDivision of Preclinical InnovationNational Center for Advancing Translational SciencesNational Institutes of HealthRockvilleMarylandUSA
| | - Ken Mackie
- Department of Psychological and Brain SciencesIndiana UniversityBloomingtonIndianaUSA
| | - Asaf Alimardanov
- Therapeutics Development BranchDivision of Preclinical InnovationNational Center for Advancing Translational SciencesNational Institutes of HealthRockvilleMarylandUSA
| | - Malliga R. Iyer
- Laboratory of Physiologic StudiesNational Institute on Alcohol Abuse and AlcoholismNational Institutes of HealthRockvilleMarylandUSA
| | - William A. Gahl
- Section of Human Biochemical GeneticsMedical Genetics BranchNational Human Genome Research InstituteNational Institutes of HealthBethesdaMarylandUSA
- NIH Undiagnosed Diseases Program and Office of the Clinical DirectorNational Human Genome Research InstituteNational Institutes of HealthBethesdaMarylandUSA
| | - George Kunos
- Laboratory of Physiologic StudiesNational Institute on Alcohol Abuse and AlcoholismNational Institutes of HealthRockvilleMarylandUSA
| | - Bernadette R. Gochuico
- Section of Human Biochemical GeneticsMedical Genetics BranchNational Human Genome Research InstituteNational Institutes of HealthBethesdaMarylandUSA
| | - May Christine V. Malicdan
- Section of Human Biochemical GeneticsMedical Genetics BranchNational Human Genome Research InstituteNational Institutes of HealthBethesdaMarylandUSA
- NIH Undiagnosed Diseases Program and Office of the Clinical DirectorNational Human Genome Research InstituteNational Institutes of HealthBethesdaMarylandUSA
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DiPatrizio NV. Endocannabinoids and the Gut-Brain Control of Food Intake and Obesity. Nutrients 2021; 13:nu13041214. [PMID: 33916974 PMCID: PMC8067588 DOI: 10.3390/nu13041214] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 04/01/2021] [Accepted: 04/02/2021] [Indexed: 02/07/2023] Open
Abstract
Gut-brain signaling controls food intake and energy homeostasis, and its activity is thought to be dysregulated in obesity. We will explore new studies that suggest the endocannabinoid (eCB) system in the upper gastrointestinal tract plays an important role in controlling gut-brain neurotransmission carried by the vagus nerve and the intake of palatable food and other reinforcers. A focus will be on studies that reveal both indirect and direct interactions between eCB signaling and vagal afferent neurons. These investigations identify (i) an indirect mechanism that controls nutrient-induced release of peptides from the gut epithelium that directly interact with corresponding receptors on vagal afferent neurons, and (ii) a direct mechanism via interactions between eCBs and cannabinoid receptors expressed on vagal afferent neurons. Moreover, the impact of diet-induced obesity on these pathways will be considered.
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Affiliation(s)
- Nicholas V DiPatrizio
- Division of Biomedical Sciences, School of Medicine, University of California Riverside, Riverside, CA 92521, USA
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30
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Farokhnia M, Abshire KM, Hammer A, Deschaine SL, Saravanakumar A, Cobbina E, You ZB, Haass-Koffler CL, Lee MR, Akhlaghi F, Leggio L. Neuroendocrine Response to Exogenous Ghrelin Administration, Combined With Alcohol, in Heavy-Drinking Individuals: Findings From a Randomized, Double-Blind, Placebo-Controlled Human Laboratory Study. Int J Neuropsychopharmacol 2021; 24:464-476. [PMID: 33560411 PMCID: PMC8278796 DOI: 10.1093/ijnp/pyab004] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Revised: 01/22/2021] [Accepted: 02/02/2021] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Accumulating evidence has established a role for the orexigenic hormone ghrelin in alcohol-seeking behaviors. Accordingly, the ghrelin system may represent a potential pharmacotherapeutic target for alcohol use disorder. Ghrelin modulates several neuroendocrine pathways, such as appetitive, metabolic, and stress-related hormones, which are particularly relevant in the context of alcohol use. The goal of the present study was to provide a comprehensive assessment of neuroendocrine response to exogenous ghrelin administration, combined with alcohol, in heavy-drinking individuals. METHODS This was a randomized, crossover, double-blind, placebo-controlled human laboratory study, which included 2 experimental alcohol administration paradigms: i.v. alcohol self-administration and i.v. alcohol clamp. Each paradigm consisted of 2 counterbalanced sessions of i.v. ghrelin or placebo administration. Repeated blood samples were collected during each session, and peripheral concentrations of the following hormones were measured: leptin, glucagon-like peptide-1, pancreatic polypeptide, gastric inhibitory peptide, insulin, insulin-like growth factor-1, cortisol, prolactin, and aldosterone. RESULTS Despite some statistical differences, findings were consistent across the 2 alcohol administration paradigms: i.v. ghrelin, compared to placebo, increased blood concentrations of glucagon-like peptide-1, pancreatic polypeptide, cortisol, and prolactin, both acutely and during the whole session. Lower levels of leptin and higher levels of aldosterone were also found during the ghrelin vs placebo session. CONCLUSION These findings, gathered from a clinically relevant sample of heavy-drinking individuals with alcohol use disorder, provide a deeper insight into the complex interplay between ghrelin and appetitive, metabolic, and stress-related neuroendocrine pathways in the context of alcohol use.
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Affiliation(s)
- Mehdi Farokhnia
- Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, Translational Addiction Medicine Branch, National Institute on Drug Abuse Intramural Research Program and National Institute on Alcohol Abuse and Alcoholism Division of Intramural Clinical and Biological Research, National Institutes of Health, Baltimore and Bethesda, Maryland, USA,Center on Compulsive Behaviors, National Institutes of Health, Bethesda, Maryland, USA,Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA
| | - Kelly M Abshire
- Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, Translational Addiction Medicine Branch, National Institute on Drug Abuse Intramural Research Program and National Institute on Alcohol Abuse and Alcoholism Division of Intramural Clinical and Biological Research, National Institutes of Health, Baltimore and Bethesda, Maryland, USA
| | - Aaron Hammer
- Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, Translational Addiction Medicine Branch, National Institute on Drug Abuse Intramural Research Program and National Institute on Alcohol Abuse and Alcoholism Division of Intramural Clinical and Biological Research, National Institutes of Health, Baltimore and Bethesda, Maryland, USA
| | - Sara L Deschaine
- Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, Translational Addiction Medicine Branch, National Institute on Drug Abuse Intramural Research Program and National Institute on Alcohol Abuse and Alcoholism Division of Intramural Clinical and Biological Research, National Institutes of Health, Baltimore and Bethesda, Maryland, USA
| | - Anitha Saravanakumar
- Clinical Pharmacokinetics Research Laboratory, Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, Rhode Island
| | | | - Zhi-Bing You
- Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, Baltimore, Maryland, USA
| | - Carolina L Haass-Koffler
- Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, Translational Addiction Medicine Branch, National Institute on Drug Abuse Intramural Research Program and National Institute on Alcohol Abuse and Alcoholism Division of Intramural Clinical and Biological Research, National Institutes of Health, Baltimore and Bethesda, Maryland, USA,Center for Alcohol and Addiction Studies, Department of Psychiatry and Human Behavior, Brown University, Providence, Rhode Island,Center for Alcohol and Addiction Studies, Department of Behavioral and Social Sciences, Brown University School of Public Health, Providence, Rhode Island
| | - Mary R Lee
- Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, Translational Addiction Medicine Branch, National Institute on Drug Abuse Intramural Research Program and National Institute on Alcohol Abuse and Alcoholism Division of Intramural Clinical and Biological Research, National Institutes of Health, Baltimore and Bethesda, Maryland, USA
| | - Fatemeh Akhlaghi
- Clinical Pharmacokinetics Research Laboratory, Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, Rhode Island
| | - Lorenzo Leggio
- Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, Translational Addiction Medicine Branch, National Institute on Drug Abuse Intramural Research Program and National Institute on Alcohol Abuse and Alcoholism Division of Intramural Clinical and Biological Research, National Institutes of Health, Baltimore and Bethesda, Maryland, USA,Center on Compulsive Behaviors, National Institutes of Health, Bethesda, Maryland, USA,Center for Alcohol and Addiction Studies, Department of Behavioral and Social Sciences, Brown University School of Public Health, Providence, Rhode Island,Medication Development Program, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, Baltimore, Maryland, USA,Division of Addiction Medicine, Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA,Department of Neuroscience, Georgetown University Medical Center, Washington DC, USA,Correspondence: Lorenzo Leggio, MD, PhD, NIDA and NIAAA, NIH, Biomedical Research Center, 251 Bayview Boulevard, Suite 200, Room 01A844, Baltimore, MD 21224 ()
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Ding JH, Jin Z, Yang XX, Lou J, Shan WX, Hu YX, Du Q, Liao QS, Xie R, Xu JY. Role of gut microbiota via the gut-liver-brain axis in digestive diseases. World J Gastroenterol 2020; 26:6141-6162. [PMID: 33177790 PMCID: PMC7596643 DOI: 10.3748/wjg.v26.i40.6141] [Citation(s) in RCA: 99] [Impact Index Per Article: 19.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Revised: 08/29/2020] [Accepted: 09/18/2020] [Indexed: 02/06/2023] Open
Abstract
The gut-brain axis is a bidirectional information interaction system between the central nervous system (CNS) and the gastrointestinal tract, in which gut microbiota plays a key role. The gut microbiota forms a complex network with the enteric nervous system, the autonomic nervous system, and the neuroendocrine and neuroimmunity of the CNS, which is called the microbiota-gut-brain axis. Due to the close anatomical and functional interaction of the gut-liver axis, the microbiota-gut-liver-brain axis has attracted increased attention in recent years. The microbiota-gut-liver-brain axis mediates the occurrence and development of many diseases, and it offers a direction for the research of disease treatment. In this review, we mainly discuss the role of the gut microbiota in the irritable bowel syndrome, inflammatory bowel disease, functional dyspepsia, non-alcoholic fatty liver disease, alcoholic liver disease, cirrhosis and hepatic encephalopathy via the gut-liver-brain axis, and the focus is to clarify the potential mechanisms and treatment of digestive diseases based on the further understanding of the microbiota-gut- liver-brain axis.
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Affiliation(s)
- Jian-Hong Ding
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi 563003, Guizhou Province, China
| | - Zhe Jin
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi 563003, Guizhou Province, China
| | - Xiao-Xu Yang
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi 563003, Guizhou Province, China
| | - Jun Lou
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi 563003, Guizhou Province, China
| | - Wei-Xi Shan
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi 563003, Guizhou Province, China
| | - Yan-Xia Hu
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi 563003, Guizhou Province, China
| | - Qian Du
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi 563003, Guizhou Province, China
| | - Qiu-Shi Liao
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi 563003, Guizhou Province, China
| | - Rui Xie
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi 563003, Guizhou Province, China
| | - Jing-Yu Xu
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi 563003, Guizhou Province, China
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Kramer J, Dick DM, King A, Ray LA, Sher KJ, Vena A, Vendruscolo LF, Acion L. Mechanisms of Alcohol Addiction: Bridging Human and Animal Studies. Alcohol Alcohol 2020; 55:603-607. [PMID: 32781467 DOI: 10.1093/alcalc/agaa068] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2019] [Revised: 06/18/2020] [Accepted: 06/19/2020] [Indexed: 12/27/2022] Open
Abstract
AIM The purpose of this brief narrative review is to address the complexities and benefits of extending animal alcohol addiction research to the human domain, emphasizing Allostasis and Incentive Sensitization, two models that inform many pre-clinical and clinical studies. METHODS The work reviewed includes a range of approaches, including: a) animal and human studies that target the biology of craving and compulsive consumption; b) human investigations that utilize alcohol self-administration and alcohol challenge paradigms, in some cases across 10 years; c) questionnaires that document changes in the positive and negative reinforcing effects of alcohol with increasing severity of addiction; and d) genomic structural equation modeling based on data from animal and human studies. RESULTS Several general themes emerge from specific study findings. First, positive reinforcement is characteristic of early stage addiction and sometimes diminishes with increasing severity, consistent with both Allostasis and Incentive Sensitization. Second, evidence is less consistent for the predominance of negative reinforcement in later stages of addiction, a key tenant of Allostasis. Finally, there are important individual differences in motivation to drink at a given point in time as well as person-specific change patterns across time. CONCLUSIONS Key constructs of addiction, like stage and reinforcement, are by necessity operationalized differently in animal and human studies. Similarly, testing the validity of addiction models requires different strategies by the two research domains. Although such differences are challenging, they are not insurmountable, and there is much to be gained in understanding and treating addiction by combining pre-clinical and clinical approaches.
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Affiliation(s)
- John Kramer
- Department of Psychiatry, University of Iowa Carver College of Medicine, 200 Hawkins Dr, 1882JPP, Iowa City, IA 52242-1009, USA
| | - Danielle M Dick
- Department of Psychology, Virginia Commonwealth University, 612 N. Lombardy St., Richmond, VA 23284, USA.,Department Human and Molecular Genetics, Virginia Commonwealth University, 806 West Franklin Street, Box 842018, Richmond, VA 23284, USA
| | - Andrea King
- Department of Psychiatry and Behavioral Neuroscience, University of Chicago, 5841 S. Maryland Ave., Room L470, Chicago, IL 60637, USA
| | - Lara A Ray
- Department of Psychology, UCLA, 1285 Franz Hall, Los Angeles, CA 90095, USA
| | - Kenneth J Sher
- Department of Psychological Sciences, University of Missouri, 210 McAlester Hall, Columbia, MO 65211, USA
| | - Ashley Vena
- Department of Psychiatry and Behavioral Neuroscience, University of Chicago, 5841 S. Maryland Ave., Room L470, Chicago, IL 60637, USA
| | - Leandro F Vendruscolo
- Neurobiology of Addiction Section, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, 251 Bayview Boulevard, Baltimore, MD 21224, USA
| | - Laura Acion
- Department of Psychiatry, University of Iowa Carver College of Medicine, 200 Hawkins Dr, 1882JPP, Iowa City, IA 52242-1009, USA.,Instituto de Cálculo, Universidad de Buenos Aires-CONICET, Intendente Güiraldes 2160, C1428EGA, Buenos Aires, Argentina
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Iyer MR, Wood CM, Kunos G. Recent progress in the discovery of ghrelin O-acyltransferase (GOAT) inhibitors. RSC Med Chem 2020; 11:1136-1144. [PMID: 33479618 PMCID: PMC7651998 DOI: 10.1039/d0md00210k] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Accepted: 08/03/2020] [Indexed: 12/29/2022] Open
Abstract
Ghrelin is a stomach-derived peptide hormone which stimulates appetite. For ghrelin to exert its orexigenic effect, octanoylation on the serine-3 residue of this gut-brain peptide is essential. The octanoylation of ghrelin is mediated by a unique acyltransferase enzyme known as ghrelin O-acyltransferase (GOAT). Thus modulating this enzyme offers viable approaches to alter feeding behaviors. Over the past decade, several small-molecule based approaches have appeared dealing with the discovery of compounds able to modulate this enzyme for the treatment of obesity and type 2 diabetes. Drug discovery efforts from academic groups and several pharmaceutical companies have fielded compounds having efficacy in altering acylated ghrelin levels in animal models but to date, compounds modulating the activity of the GOAT enzyme do not yet represent clinical options. This mini-review covers the drug discovery approaches of the last decade since the discovery of the GOAT enzyme.
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Affiliation(s)
- Malliga R Iyer
- Medicinal Chemistry Core and Laboratory of Physiologic Studies , National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health (NIAAA/NIH) , 5625 Fishers Lane , Rockville , MD 20852 , USA . ; Tel: +301 443 2807
| | - Casey M Wood
- Medicinal Chemistry Core and Laboratory of Physiologic Studies , National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health (NIAAA/NIH) , 5625 Fishers Lane , Rockville , MD 20852 , USA . ; Tel: +301 443 2807
| | - George Kunos
- Medicinal Chemistry Core and Laboratory of Physiologic Studies , National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health (NIAAA/NIH) , 5625 Fishers Lane , Rockville , MD 20852 , USA . ; Tel: +301 443 2807
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Avalos B, Argueta DA, Perez PA, Wiley M, Wood C, DiPatrizio NV. Cannabinoid CB 1 Receptors in the Intestinal Epithelium Are Required for Acute Western-Diet Preferences in Mice. Nutrients 2020; 12:nu12092874. [PMID: 32962222 PMCID: PMC7551422 DOI: 10.3390/nu12092874] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2020] [Revised: 09/16/2020] [Accepted: 09/17/2020] [Indexed: 01/12/2023] Open
Abstract
The endocannabinoid system plays an important role in the intake of palatable food. For example, endocannabinoid signaling in the upper small-intestinal epithelium is increased (i) in rats after tasting dietary fats, which promotes intake of fats, and (ii) in a mouse model of diet-induced obesity, which promotes overeating via impaired nutrient-induced gut-brain satiation signaling. We now utilized a combination of genetic, pharmacological, and behavioral approaches to identify roles for cannabinoid CB1Rs in upper small-intestinal epithelium in preferences for a western-style diet (WD, high-fat/sucrose) versus a standard rodent diet (SD, low-fat/no sucrose). Mice were maintained on SD in automated feeding chambers. During testing, mice were given simultaneous access to SD and WD, and intakes were recorded. Mice displayed large preferences for the WD, which were inhibited by systemic pretreatment with the cannabinoid CB1R antagonist/inverse agonist, AM251, for up to 3 h. We next used our novel intestinal epithelium-specific conditional cannabinoid CB1R-deficient mice (IntCB1-/-) to investigate if intestinal CB1Rs are necessary for WD preferences. Similar to AM251 treatment, preferences for WD were largely absent in IntCB1-/- mice when compared to control mice for up to 6 h. Together, these data suggest that CB1Rs in the murine intestinal epithelium are required for acute WD preferences.
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Affiliation(s)
- Bryant Avalos
- Division of Biomedical Sciences, School of Medicine, University of California, Riverside, Riverside, CA 92521, USA; (B.A.); (D.A.A.); (P.A.P.); (M.W.); (C.W.)
| | - Donovan A. Argueta
- Division of Biomedical Sciences, School of Medicine, University of California, Riverside, Riverside, CA 92521, USA; (B.A.); (D.A.A.); (P.A.P.); (M.W.); (C.W.)
- Department of Medicine, School of Medicine, University of California, Irvine, Irvine, CA 92697, USA
| | - Pedro A. Perez
- Division of Biomedical Sciences, School of Medicine, University of California, Riverside, Riverside, CA 92521, USA; (B.A.); (D.A.A.); (P.A.P.); (M.W.); (C.W.)
| | - Mark Wiley
- Division of Biomedical Sciences, School of Medicine, University of California, Riverside, Riverside, CA 92521, USA; (B.A.); (D.A.A.); (P.A.P.); (M.W.); (C.W.)
| | - Courtney Wood
- Division of Biomedical Sciences, School of Medicine, University of California, Riverside, Riverside, CA 92521, USA; (B.A.); (D.A.A.); (P.A.P.); (M.W.); (C.W.)
| | - Nicholas V. DiPatrizio
- Division of Biomedical Sciences, School of Medicine, University of California, Riverside, Riverside, CA 92521, USA; (B.A.); (D.A.A.); (P.A.P.); (M.W.); (C.W.)
- Correspondence: ; Tel.: +1-951-827-7252
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Stasiulewicz A, Znajdek K, Grudzień M, Pawiński T, Sulkowska JI. A Guide to Targeting the Endocannabinoid System in Drug Design. Int J Mol Sci 2020; 21:ijms21082778. [PMID: 32316328 PMCID: PMC7216112 DOI: 10.3390/ijms21082778] [Citation(s) in RCA: 78] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2020] [Revised: 04/07/2020] [Accepted: 04/14/2020] [Indexed: 12/11/2022] Open
Abstract
The endocannabinoid system (ECS) is one of the most crucial systems in the human organism, exhibiting multi-purpose regulatory character. It is engaged in a vast array of physiological processes, including nociception, mood regulation, cognitive functions, neurogenesis and neuroprotection, appetite, lipid metabolism, as well as cell growth and proliferation. Thus, ECS proteins, including cannabinoid receptors and their endogenous ligands’ synthesizing and degrading enzymes, are promising therapeutic targets. Their modulation has been employed in or extensively studied as a treatment of multiple diseases. However, due to a complex nature of ECS and its crosstalk with other biological systems, the development of novel drugs turned out to be a challenging task. In this review, we summarize potential therapeutic applications for ECS-targeting drugs, especially focusing on promising synthetic compounds and preclinical studies. We put emphasis on modulation of specific proteins of ECS in different pathophysiological areas. In addition, we stress possible difficulties and risks and highlight proposed solutions. By presenting this review, we point out information pivotal in the spotlight of ECS-targeting drug design, as well as provide an overview of the current state of knowledge on ECS-related pharmacodynamics and show possible directions for needed research.
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Affiliation(s)
- Adam Stasiulewicz
- Department of Drug Chemistry, Faculty of Pharmacy, Medical University of Warsaw, Banacha 1, 02-097 Warsaw, Poland; (M.G.); (T.P.)
- Interdisciplinary Laboratory of Biological Systems Modelling, Centre of New Technologies, University of Warsaw, Banacha 2c, 02-097 Warsaw, Poland;
- Correspondence: (A.S.); (J.I.S.)
| | - Katarzyna Znajdek
- Interdisciplinary Laboratory of Biological Systems Modelling, Centre of New Technologies, University of Warsaw, Banacha 2c, 02-097 Warsaw, Poland;
- Faculty of Pharmacy, Medical University of Warsaw, Banacha 1, 02-097 Warsaw, Poland
| | - Monika Grudzień
- Department of Drug Chemistry, Faculty of Pharmacy, Medical University of Warsaw, Banacha 1, 02-097 Warsaw, Poland; (M.G.); (T.P.)
| | - Tomasz Pawiński
- Department of Drug Chemistry, Faculty of Pharmacy, Medical University of Warsaw, Banacha 1, 02-097 Warsaw, Poland; (M.G.); (T.P.)
| | - Joanna I. Sulkowska
- Interdisciplinary Laboratory of Biological Systems Modelling, Centre of New Technologies, University of Warsaw, Banacha 2c, 02-097 Warsaw, Poland;
- Faculty of Chemistry, University of Warsaw, Pasteura 1, 02-093 Warsaw, Poland
- Materials and Process Simulation Center, California Institute of Technology, Pasadena, CA 91125, USA
- Correspondence: (A.S.); (J.I.S.)
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Peris J, Steck MR, Krause EG. Oxytocin treatment for alcoholism: Potential neurocircuitry targets. Neuropharmacology 2020; 171:108091. [PMID: 32304701 DOI: 10.1016/j.neuropharm.2020.108091] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2019] [Revised: 03/19/2020] [Accepted: 04/03/2020] [Indexed: 12/19/2022]
Abstract
Oxytocin (OT) has gained considerable interest in recent years as a potential treatment for alcoholism and other substance use disorders. Evidence continues to mount that OT administered either centrally, peripherally or intranasally can decrease ethanol intake in both humans and animal models. The potential mechanisms for the ability of OT to decrease ethanol reward, and importantly, cue- and stress-induced ethanol relapse, are explored by reviewing the specific neuronal circuits involved in mediating these actions and their sensitivity to OT. In addition to dopamine neurons that project from ventral tegmental area (VTA) to nucleus accumbens (NAc) to signal positively reinforcing events, OT receptors (OxTR) are also expressed by dopamine neurons that project from VTA to brain regions that can convey aversive properties of a stimulus. Moreover, OxTR are expressed by non-dopaminergic neurons in the VTA, such as GABA and glutamate neurons, which can both modulate the activity of dopamine VTA neurons locally (in opposite directions) or can project to other brain regions, including the NAc, where it can alter either positive reinforcement or aversion caused by ethanol. The ability of OT to regulate limbic circuitry and the hypothalamic-pituitary-adrenal axis is discussed as a potential mechanism for the ability of OT to inhibit ethanol-induced negative reinforcement. Together, understanding the diversity and complexity of OT regulation of ethanol reward may contribute to more effective use of OT as pharmacotherapy for alcohol use disorder. This article is part of the special issue on Neuropeptides.
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Affiliation(s)
- Joanna Peris
- Department of Pharmacodynamics, University of Florida, Gainesville, FL, 32610, USA.
| | - Madeline R Steck
- Department of Pharmacodynamics, University of Florida, Gainesville, FL, 32610, USA
| | - Eric G Krause
- Department of Pharmacodynamics, University of Florida, Gainesville, FL, 32610, USA
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The therapeutic potential of second and third generation CB1R antagonists. Pharmacol Ther 2020; 208:107477. [DOI: 10.1016/j.pharmthera.2020.107477] [Citation(s) in RCA: 59] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2019] [Accepted: 01/02/2020] [Indexed: 12/25/2022]
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Kunos G. Interactions Between Alcohol and the Endocannabinoid System. Alcohol Clin Exp Res 2020; 44:790-805. [PMID: 32056226 DOI: 10.1111/acer.14306] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2019] [Accepted: 02/05/2020] [Indexed: 12/12/2022]
Abstract
Endocannabinoids are lipid mediators that interact with the same cannabinoid receptors that recognize Δ9 -tetrahydrocannabinol (THC), the psychoactive constituent of marijuana, to induce similar effects in the brain and periphery. Alcohol and THC are both addictive substances whose acute use elicits rewarding effects that can lead to chronic and compulsive use via engaging similar signaling pathways in the brain. In the liver, both alcohol and endocannabinoids activate lipogenic gene expression leading to fatty liver disease. This review focuses on evidence accumulated over the last 2 decades to indicate that both the addictive neural effects of ethanol and its organ toxic effects in the liver and elsewhere are mediated, to a large extent, by endocannabinoids signaling via cannabinoid-1 receptors (CB1 R). The therapeutic potential of CB1 R blockade globally or in peripheral tissues only is also discussed.
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Affiliation(s)
- George Kunos
- From the, Division of Clinical and Biological Research, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland
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Neasta J, Darcq E, Jeanblanc J, Carnicella S, Ben Hamida S. GPCR and Alcohol-Related Behaviors in Genetically Modified Mice. Neurotherapeutics 2020; 17:17-42. [PMID: 31919661 PMCID: PMC7007453 DOI: 10.1007/s13311-019-00828-y] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
G protein-coupled receptors (GPCRs) constitute the largest class of cell surface signaling receptors and regulate major neurobiological processes. Accordingly, GPCRs represent primary targets for the treatment of brain disorders. Several human genetic polymorphisms affecting GPCRs have been associated to different components of alcohol use disorder (AUD). Moreover, GPCRs have been reported to contribute to several features of alcohol-related behaviors in animal models. Besides traditional pharmacological tools, genetic-based approaches mostly aimed at deleting GPCR genes provided substantial information on how key GPCRs drive alcohol-related behaviors. In this review, we summarize the alcohol phenotypes that ensue from genetic manipulation, in particular gene deletion, of key GPCRs in rodents. We focused on GPCRs that belong to fundamental neuronal systems that have been shown as potential targets for the development of AUD treatment. Data are reviewed with particular emphasis on alcohol reward, seeking, and consumption which are behaviors that capture essential aspects of AUD. Literature survey indicates that in most cases, there is still a gap in defining the intracellular transducers and the functional crosstalk of GPCRs as well as the neuronal populations in which their signaling regulates alcohol actions. Further, the implication of only a few orphan GPCRs has been so far investigated in animal models. Combining advanced pharmacological technologies with more specific genetically modified animals and behavioral preclinical models is likely necessary to deepen our understanding in how GPCR signaling contributes to AUD and for drug discovery.
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Affiliation(s)
- Jérémie Neasta
- Laboratoire de Pharmacologie, Faculté de Pharmacie, University of Montpellier, 34093, Montpellier, France
| | - Emmanuel Darcq
- Douglas Hospital Research Center, Department of Psychiatry, McGill University, 6875 Boulevard LaSalle, Montreal, Quebec, H4H 1R3, Canada
| | - Jérôme Jeanblanc
- Research Group on Alcohol and Pharmacodependences-INSERM U1247, University of Picardie Jules Verne, 80025, Amiens, France
| | - Sebastien Carnicella
- INSERM U1216, Grenoble Institut des Neurosciences (GIN), University of Grenoble Alpes, 38000, Grenoble, France
| | - Sami Ben Hamida
- Douglas Hospital Research Center, Department of Psychiatry, McGill University, 6875 Boulevard LaSalle, Montreal, Quebec, H4H 1R3, Canada.
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Argemi J, Bataller R. Hepatocyte-stellate cell synapse in alcohol-induced steatosis: another role for endocannabinoids. Nat Rev Gastroenterol Hepatol 2020; 17:5-6. [PMID: 31686014 PMCID: PMC7608945 DOI: 10.1038/s41575-019-0233-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/08/2022]
Abstract
A new study demonstrates a novel role for an endocannabinoid in promoting hepatocyte steatosis. The study describes a mode of bidirectional communication between the alcohol-injured hepatocyte and the glutamate-activated hepatic stellate cell. This intercellular communication represents a novel targetable pathogenic mechanism that could lead to new strategies to prevent fatty liver disease progression to cirrhosis.
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Abstract
Substance use disorder (SUD) is a major public health crisis worldwide, and effective treatment options are limited. During the past 2 decades, researchers have investigated the impact of a variety of pharmacological approaches to treat SUD, one of which is the use of medical cannabis or cannabinoids. Significant progress was made with the discovery of rimonabant, a selective CB1 receptor (CB1R) antagonist (also an inverse agonist), as a promising therapeutic for SUDs and obesity. However, serious adverse effects such as depression and suicidality led to the withdrawal of rimonabant (and almost all other CB1R antagonists/inverse agonists) from clinical trials worldwide in 2008. Since then, much research interest has shifted to other cannabinoid-based strategies, such as peripheral CB1R antagonists/inverse agonists, neutral CB1R antagonists, allosteric CB1R modulators, CB2R agonists, fatty acid amide hydrolase (FAAH) inhibitors, monoacylglycerol lipase (MAGL) inhibitors, fatty acid binding protein (FABP) inhibitors, or nonaddictive phytocannabinoids with CB1R or CB2R-binding profiles, as new therapeutics for SUDs. In this article, we first review recent progress in research regarding the endocannabinoid systems, cannabis reward versus aversion, and the underlying receptor mechanisms. We then review recent progress in cannabinoid-based medication development for the treatment of SUDs. As evidence continues to accumulate, neutral CB1R antagonists (such as AM4113), CB2R agonists (JWH133, Xie2-64), and nonselective phytocannabinoids (cannabidiol, β-caryophyllene, ∆9-tetrahydrocannabivarin) have shown great therapeutic potential for SUDs, as shown in experimental animals. Several cannabinoid-based medications (e.g., dronabinol, nabilone, PF-04457845) that entered clinical trials have shown promising results in reducing withdrawal symptoms in cannabis and opioid users.
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Affiliation(s)
- Ewa Galaj
- Addiction Biology Unit, Molecular Targets and Medication Discoveries Branch, Intramural Research Program, National Institute on Drug Abuse, Baltimore, MD, 21224, USA
| | - Zheng-Xiong Xi
- Addiction Biology Unit, Molecular Targets and Medication Discoveries Branch, Intramural Research Program, National Institute on Drug Abuse, Baltimore, MD, 21224, USA.
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Mani BK, Castorena CM, Vianna CR, Lee CE, Metzger NP, Vijayaraghavan P, Osborne-Lawrence S, Elmquist JK, Zigman JM. Combined Loss of Ghrelin Receptor and Cannabinoid CB1 Receptor in Mice Decreases Survival but does not Additively Reduce Body Weight or Eating. Neuroscience 2019; 447:53-62. [PMID: 31520709 DOI: 10.1016/j.neuroscience.2019.09.005] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2019] [Revised: 08/28/2019] [Accepted: 09/02/2019] [Indexed: 01/08/2023]
Abstract
Ghrelin administration increases food intake, body weight (BW), adiposity, and blood glucose. In contrast, although mouse models lacking ghrelin or its receptor (Growth Hormone Secretagogue Receptor (GHSR)) exhibit life-threatening hypoglycemia in starvation-like states, they do not exhibit appreciable reductions in food intake, BW, adiposity, blood glucose, or survival when food availability is unrestricted. This suggests the existence of a parallel neuromodulatory system that can compensate for disruptions in the ghrelin system in certain settings. Here, we hypothesized that the cannabinoid CB1 receptor (CB1R) may encode this putative redundancy, and as such, that genetic deletion of both GHSR and CB1R would exaggerate the metabolic deficits associated with deletion of GHSR alone. To test this hypothesis, we assessed food intake, BW, blood glucose, survival, and plasma acyl-ghrelin in ad libitum-fed male wild-type mice and those that genetically lack GHSR (GHSR-nulls), CB1R (CB1R-nulls), or both GHSR and CB1R (double-nulls). BW, fat mass, and lean mass were similar in GHSR-nulls and wild-types, lower in CB1R-nulls, but not further reduced in double-nulls. Food intake, plasma acyl-ghrelin, and blood glucose were similar among genotypes. Deletion of either GHSR or CB1R alone did not have a statistically-significant effect on survival, but double-nulls demonstrated a statistical trend towards decreased survival (p = 0.07). We conclude that CB1R is not responsible for the normal BW, adiposity, food intake, and blood glucose observed in GHSR-null mice in the setting of unrestricted food availability. Nor is CB1R required for plasma acyl-ghrelin secretion in that setting. However, GHSR may be protective against exaggerated mortality associated with CB1R deletion.
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Affiliation(s)
- Bharath K Mani
- Center for Hypothalamic Research, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Carlos M Castorena
- Center for Hypothalamic Research, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Claudia R Vianna
- Center for Hypothalamic Research, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Charlotte E Lee
- Center for Hypothalamic Research, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Nathan P Metzger
- Center for Hypothalamic Research, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Prasanna Vijayaraghavan
- Center for Hypothalamic Research, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Sherri Osborne-Lawrence
- Center for Hypothalamic Research, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Joel K Elmquist
- Center for Hypothalamic Research, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA; Division of Endocrinology & Metabolism, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA; Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX, USA; Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Jeffrey M Zigman
- Center for Hypothalamic Research, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA; Division of Endocrinology & Metabolism, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA; Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX, USA.
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Rasineni K, Casey CA, Kharbanda KK. Reply to "Letter to Editor: Chronic alcohol exposure alters circulating insulin and ghrelin levels in hepatic steatosis: a translational research perspective". Am J Physiol Gastrointest Liver Physiol 2019; 317:G361-G362. [PMID: 31461305 PMCID: PMC6774088 DOI: 10.1152/ajpgi.00143.2019] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2019] [Accepted: 06/03/2019] [Indexed: 01/31/2023]
Affiliation(s)
- Karuna Rasineni
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, Nebraska
| | - Carol A Casey
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, Nebraska
| | - Kusum K Kharbanda
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, Nebraska
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