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Lu XF, Zhang HW, Chang X, Guo YZ. F-box protein 22: A prognostic biomarker for colon cancer associated with immune infiltration and chemotherapy resistance. World J Gastrointest Oncol 2025; 17:102913. [PMID: 40235877 PMCID: PMC11995338 DOI: 10.4251/wjgo.v17.i4.102913] [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: 11/28/2024] [Revised: 01/10/2025] [Accepted: 02/21/2025] [Indexed: 03/25/2025] Open
Abstract
BACKGROUND Colon cancer represents a significant malignant neoplasm within the digestive system, characterized by a high incidence rate and substantial disease burden. The F-box protein 22 (FBXO22) plays a role in forming a specific type of ubiquitin ligase subunit, which is expressed abnormally in various malignant neoplasms and shows a notable relationship with prognosis in patients with cancer. Nevertheless, the function of FBXO22 in the context of colon cancer remains inadequately elucidated. AIM To explore the role of FBXO22 in colon cancer by examining FBXO22 expression patterns and analyzing how the protein affects the prognosis in patients who have undergone surgery. METHODS Samples of cancerous and nearby normal tissues from patients with colon cancer were gathered, along with pertinent clinical data. Expression levels of the FBXO22 gene in both cancerous and paracancerous tissues were assessed through immunohistochemistry. The median H score served as a criterion for categorizing FBXO22 gene expression into high and low levels in cancerous tissues, and the relationship between these expression levels and various pathologic characteristics of patients, such as age, sex, and clinical stage, was analyzed. Colon cancer cell lines HCT116 and DLD-1 were used and divided into three groups: A blank control group, a negative control group, and a si-FBXO22 group. FBXO22 gene mRNA and protein expression were measured 24 hours post-transfection using real-time fluorescence quantitative polymerase chain reaction and western blotting. The proliferation capabilities of the cells in each group were assessed using the Cell Counting Kit-8 assay and 5-ethynyl-2'-deoxyuridine assay, while cellular migration and invasion abilities were evaluated using scratch healing and Transwell assays. Various online platforms, including the Timer Immune Estimation Resource, were used to analyze pan-cancer expression, promoter methylation levels, and mutation frequencies of the FBXO22 gene in colon cancer patients. Additionally, the correlation between FBXO22 gene expression, patient prognosis, immune cell infiltration, and the expression of immune molecules in the colon cancer microenvironment was investigated. The relationship between FBXO22 gene expression and chemotherapy resistance, along with the potential mechanisms of action of the FBXO22 gene, were analyzed using The Cancer Genome Atlas dataset and the Genomics of Drug Sensitivity in Cancer drug training set via R software. RESULTS Compared with normal colonic tissues, the FBXO22 gene was highly expressed in colon cancer tissues. Post-operative patients with colon cancer elevated FBXO22 reduced survival and exhibited resistance to various chemotherapeutic agents. FBXO22 expression suppresses the infiltration of anti-tumor immune cells. In vitro, FBXO22 knockdown inhibited the proliferation and migration of colon cancer cells. CONCLUSION The FBXO22 gene is a biomarker of poor prognosis in patients with colon cancer and has potential as a target for immunotherapy and overcoming chemotherapy resistance.
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Affiliation(s)
- Xiao-Fei Lu
- Department of Clinical Medicine, Hebei University of Engineering, Handan 056002, Hebei Province, China
| | - Hong-Wei Zhang
- Department of Gastroenterology, Affiliated Hospital of Hebei Engineering University, Handan 056002, Hebei Province, China
| | - Xiao Chang
- Department of Gastroenterology, Affiliated Hospital of Hebei Engineering University, Handan 056002, Hebei Province, China
| | - Yong-Ze Guo
- Department of Gastroenterology, Affiliated Hospital of Hebei Engineering University, Handan 056002, Hebei Province, China
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Liu L, Song FH, Gao SJ, Wu JY, Li DY, Zhang LQ, Zhou YQ, Liu DQ, Mei W. Peroxisome proliferator-activated receptor gamma: A promising therapeutic target for the treatment of chronic pain. Brain Res 2025; 1850:149366. [PMID: 39617285 DOI: 10.1016/j.brainres.2024.149366] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2024] [Revised: 11/13/2024] [Accepted: 11/28/2024] [Indexed: 12/12/2024]
Abstract
Chronic pain represents an incapacitating medical condition that profoundly impacts the patients' quality of life. Managing chronic pain poses a significant challenge for healthcare professionals due to its multifaceted nature and the limited effectiveness of current treatment options. Therefore, novel therapeutic interventions are crucially required for the management of chronic pain. Peroxisome proliferator-activated receptor gamma (PPARγ), a nuclear receptor, exerts regulatory effects on physiological processes such as glucose and lipid metabolism. Emerging studies demonstrate that PPARγ is a critical regulator of the expression of various genes, including those of anti-inflammatory cytokines and antioxidant enzymes. Substantial evidence indicates decreased expression of PPARγ in the sciatic nerve, dorsal root ganglia, and spinal cord dorsal horn in animal models of chronic pain. Furthermore, natural or synthetic PPARγ agonists had inhibitory effects on nociceptive hypersensitivity in various animal models of chronic pain. This review summarizes and discusses preclinical evidence demonstrating the therapeutic potential of PPARγ agonists in chronic pain management. The available evidence indicates that PPARγ activation reduces chronic pain by inhibiting neuroinflammation and oxidative stress as well as modulation of opioidergic system. Overall, the use of PPARγ agonists is a promising therapeutic approach for treating chronic pain; however, further research regarding its detailed mechanisms is warranted.
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Affiliation(s)
- Lin Liu
- Department of Anesthesiology and Pain Medicine, Hubei Key Laboratory of Geriatric Anesthesia and Perioperative Brain Health, and Wuhan Clinical Research Center for Geriatric Anesthesia, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, China
| | - Fan-He Song
- Department of Anesthesiology and Pain Medicine, Hubei Key Laboratory of Geriatric Anesthesia and Perioperative Brain Health, and Wuhan Clinical Research Center for Geriatric Anesthesia, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, China
| | - Shao-Jie Gao
- Department of Anesthesiology and Pain Medicine, Hubei Key Laboratory of Geriatric Anesthesia and Perioperative Brain Health, and Wuhan Clinical Research Center for Geriatric Anesthesia, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, China
| | - Jia-Yi Wu
- Department of Anesthesiology and Pain Medicine, Hubei Key Laboratory of Geriatric Anesthesia and Perioperative Brain Health, and Wuhan Clinical Research Center for Geriatric Anesthesia, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, China
| | - Dan-Yang Li
- Department of Anesthesiology and Pain Medicine, Hubei Key Laboratory of Geriatric Anesthesia and Perioperative Brain Health, and Wuhan Clinical Research Center for Geriatric Anesthesia, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, China
| | - Long-Qing Zhang
- Department of Anesthesiology and Pain Medicine, Hubei Key Laboratory of Geriatric Anesthesia and Perioperative Brain Health, and Wuhan Clinical Research Center for Geriatric Anesthesia, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, China
| | - Ya-Qun Zhou
- Department of Anesthesiology and Pain Medicine, Hubei Key Laboratory of Geriatric Anesthesia and Perioperative Brain Health, and Wuhan Clinical Research Center for Geriatric Anesthesia, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, China
| | - Dai-Qiang Liu
- Department of Anesthesiology and Pain Medicine, Hubei Key Laboratory of Geriatric Anesthesia and Perioperative Brain Health, and Wuhan Clinical Research Center for Geriatric Anesthesia, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, China.
| | - Wei Mei
- Department of Anesthesiology and Pain Medicine, Hubei Key Laboratory of Geriatric Anesthesia and Perioperative Brain Health, and Wuhan Clinical Research Center for Geriatric Anesthesia, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, China.
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Segelcke D, Sondermann JR, Kappert C, Pradier B, Görlich D, Fobker M, Vollert J, Zahn PK, Schmidt M, Pogatzki-Zahn EM. Blood proteomics and multimodal risk profiling of human volunteers after incision injury: A translational study for advancing personalized pain management after surgery. Pharmacol Res 2025; 212:107580. [PMID: 39756555 DOI: 10.1016/j.phrs.2025.107580] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2024] [Revised: 01/01/2025] [Accepted: 01/02/2025] [Indexed: 01/07/2025]
Abstract
A significant number of patients develop chronic pain after surgery, but prediction of those who are at risk is currently not possible. Thus, prognostic prediction models that include bio-psycho-social and physiological factors in line with the complex nature of chronic pain would be urgently required. Here, we performed a translational study in male volunteers before and after an experimental incision injury. We determined multi-modal features ranging from pain characteristics and psychological questionnaires to blood plasma proteomics. Outcome measures included pain intensity ratings and the extent of the area of hyperalgesia to mechanical stimuli surrounding the incision, as a proxy of central sensitization. A multi-step logistic regression analysis was performed to predict outcome measures based on feature combinations using data-driven cross-validation and prognostic model development. Phenotype-based stratification resulted in the identification of low and high responders for both outcome measures. Regression analysis revealed prognostic proteomic, specific psychophysical, and psychological features. A combinatorial set of distinct features enabled us to predict outcome measures with increased accuracy compared to using single features. Remarkably, in high responders, protein network analysis suggested a protein signature characteristic of low-grade inflammation. Alongside, in silico drug repurposing highlighted potential treatment options employing antidiabetic and anti-inflammatory drugs. Taken together, we present here an integrated pipeline that harnesses bio-psycho-physiological data for prognostic prediction in a translational approach. This pipeline opens new avenues for clinical application with the goal of stratifying patients and identifying potential new targets, as well as mechanistic correlates, for postsurgical pain.
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Affiliation(s)
- Daniel Segelcke
- Department of Anaesthesiology, Intensive Care and Pain Medicine, University Hospital Muenster, Albert-Schweitzer-Campus 1, Muenster 44651, Germany
| | - Julia R Sondermann
- Department of Pharmaceutical Sciences, Division of Pharmacology and Toxicology, Systems Biology of Pain Group, University of Vienna, UZA II, Josef-Holaubek-Platz 2, Vienna A-1090, Austria
| | - Christin Kappert
- Max-Planck Institute for Multidisciplinary Sciences, City Campus, Hermann-Rein-Straße 3, Göttingen 37075, Germany
| | - Bruno Pradier
- Department of Anaesthesiology, Intensive Care and Pain Medicine, University Hospital Muenster, Muenster, Germany
| | - Dennis Görlich
- Institute of Biostatistics and Clinical Research, University of Münster, Albert-Schweitzer-Campus 1, Münster 44651, Germany
| | - Manfred Fobker
- Centre of Laboratory Medicine, University Hospital Muenster, Albert-Schweitzer-Campus 1, Muenster 44651, Germany
| | - Jan Vollert
- Department of Anaesthesiology, Intensive Care and Pain Medicine, University Hospital Muenster, Albert-Schweitzer-Campus 1, Muenster 44651, Germany; Department of Clinical and Biomedical Sciences, Faculty of Health and Life Sciences, University of Exeter, Exeter, UK
| | - Peter K Zahn
- Department of Anesthesiology, Intensive Care and Pain Medicine, BG University Hospital Bergmannsheil, Ruhr-Universität Bochum, Bürkle de la Camp-Platz 1, Bochum 44789, Germany
| | - Manuela Schmidt
- Department of Pharmaceutical Sciences, Division of Pharmacology and Toxicology, Systems Biology of Pain Group, University of Vienna, UZA II, Josef-Holaubek-Platz 2, Vienna A-1090, Austria.
| | - Esther M Pogatzki-Zahn
- Department of Anaesthesiology, Intensive Care and Pain Medicine, University Hospital Muenster, Albert-Schweitzer-Campus 1, Muenster 44651, Germany.
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Jabbari S, Zakaria ZA, de Menezes IRA, Mohammadi S. Antinociceptive, antineuropathic, and antimigraine-like activities ofFritillariaimperialis L. rich in verticinone on rats: Mechanisms of action. JOURNAL OF ETHNOPHARMACOLOGY 2025; 339:119174. [PMID: 39613005 DOI: 10.1016/j.jep.2024.119174] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/02/2024] [Revised: 11/26/2024] [Accepted: 11/27/2024] [Indexed: 12/01/2024]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Fritillaria imperialis L. (Fabaceae), commonly known as "Laleh vazhgon", ethnomedicinally utilized in Iranian traditional medicine to treat joint pain, chronic daily headaches, and back pain. AIM OF THE STUDY To investigate the antinociceptive, anti-neuropathic, and anti-migraine activities of Fritillaria imperialis bulbs essential oil (FIEO) as well as to uncover the potential mechanisms of action involved. MATERIALS AND METHODS The antinociceptive activity of FIEO and its main constituent, Verticinone (Vt), was assessed using the formalin-induced paw licking assay. The potential mechanisms of antinociception were investigated through various antagonists. Additionally, their antineuropathic activity was examined using the cervical spinal cord contusion (CCS) technique and the possible role of Stat3 was evaluated using Western blot analysis. The nitroglycerin-induced model (NTG) was also employed for the evaluation of migraine. RESULTS FIEO demonstrated significant antinociceptive activity in both phases of the formalin-induced test. However, the FIEO activity was more pronounced effect observed in the second phase. Modulators of the NO-cGMP-K+ channel pathway significantly reversed the antinociceptive activity of FIEO (P < 0.05). Additionally, antagonists of TRPV1, PPARα, dopamine D1, GABAA, and δ-opioid receptors also significantly reversed the antinociceptive effects of FIEO (P < 0.05). In a separate study, both FIEO and Vt were found to attenuate hyperalgesia and mechanical allodynia (P < 0.01) when evaluated using the CCS-induced pain model. Furthermore, FIEO may alleviate migraine behaviors, likely related to the regulation of NO and CGRP levels. CONCLUSION FIEO exerts an antineuropathic effect through the phosphorylation of Stat3. Furthermore, the antinociceptive activity is partially modulated via the NO-cGMP-K+ channel pathway, as well as the activation of TRPV, PPAR, opioid, and GABA receptors. Vt may be involved in the antinociceptive, antineuropathic, and antimigraine activities induced by FIEO.
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Affiliation(s)
- Sajjad Jabbari
- Department of Biology, Faculty of Sciences, Islamic Azad University, Tehran North Branch, Tehran, Iran.
| | - Zainul Amiruddin Zakaria
- Borneo Research on Algesia, Inflammation and Neurodegeneration (BRAIN) Group, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Universiti Malaysia Sabah, Jalan UMS, Kota Kinabalu, 88400, Sabah, Malaysia; Department of Pharmaceutical Sciences, Faculty of Pharmacy, Universitas Airlangga, Gedung Nanizar Zaman Joenoes Kampus C, Jl. Mulyorejo, Mulyorejo, Surabaya, East Java 60115, Indonesia.
| | - Irwin Rose Alencar de Menezes
- Laboratory of Pharmacology and Molecular Chemistry, Department of Chemical Biology, Regional University of Cariri (URCA), Rua Coronel Antônio Luis 1161, Pimenta, CEP 63105-000, Crato, Ceará, Brazil.
| | - Saeed Mohammadi
- Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran.
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Sokolaj E, Assareh N, Anderson K, Aubrey KR, Vaughan CW. Cannabis constituents for chronic neuropathic pain; reconciling the clinical and animal evidence. J Neurochem 2024; 168:3685-3698. [PMID: 37747128 DOI: 10.1111/jnc.15964] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Revised: 08/29/2023] [Accepted: 09/04/2023] [Indexed: 09/26/2023]
Abstract
Chronic neuropathic pain is a debilitating pain syndrome caused by damage to the nervous system that is poorly served by current medications. Given these problems, clinical studies have pursued extracts of the plant Cannabis sativa as alternative treatments for this condition. The vast majority of these studies have examined cannabinoids which contain the psychoactive constituent delta-9-tetrahydrocannabinol (THC). While there have been some positive findings, meta-analyses of this clinical work indicates that this effectiveness is limited and hampered by side-effects. This review focuses on how recent preclinical studies have predicted the clinical limitations of THC-containing cannabis extracts, and importantly, point to how they might be improved. This work highlights the importance of targeting channels and receptors other than cannabinoid CB1 receptors which mediate many of the side-effects of cannabis.
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Affiliation(s)
- Eddy Sokolaj
- Pain Management Research Institute, Kolling Institute of Medical Research, Northern Clinical School, Royal North Shore Hospital, University of Sydney, Sydney, New South Wales, Australia
| | - Neda Assareh
- Pain Management Research Institute, Kolling Institute of Medical Research, Northern Clinical School, Royal North Shore Hospital, University of Sydney, Sydney, New South Wales, Australia
| | - Kristen Anderson
- Pain Management Research Institute, Kolling Institute of Medical Research, Northern Clinical School, Royal North Shore Hospital, University of Sydney, Sydney, New South Wales, Australia
| | - Karin R Aubrey
- Pain Management Research Institute, Kolling Institute of Medical Research, Northern Clinical School, Royal North Shore Hospital, University of Sydney, Sydney, New South Wales, Australia
| | - Christopher W Vaughan
- Pain Management Research Institute, Kolling Institute of Medical Research, Northern Clinical School, Royal North Shore Hospital, University of Sydney, Sydney, New South Wales, Australia
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Alexander SN, Green AR, Debner EK, Ramos Freitas LE, Abdelhadi HMK, Szabo-Pardi TA, Burton MD. The influence of sex on neuroimmune communication, pain, and physiology. Biol Sex Differ 2024; 15:82. [PMID: 39439003 PMCID: PMC11494817 DOI: 10.1186/s13293-024-00660-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2024] [Accepted: 10/02/2024] [Indexed: 10/25/2024] Open
Abstract
With the National Institutes of Health's mandate to consider sex as a biological variable (SABV), there has been a significant increase of studies utilizing both sexes. Historically, we have known that biological sex and hormones influence immunological processes and now studies focusing on interactions between the immune, endocrine, and nervous systems are revealing sex differences that influence pain behavior and various molecular and biochemical processes. Neuroendocrine-immune interactions represent a key integrative discipline that will reveal critical processes in each field as it pertains to novel mechanisms in sex differences and necessary therapeutics. Here we appraise preclinical and clinical literature to discuss these interactions and key pathways that drive cell- and sex-specific differences in immunity, pain, and physiology.
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Affiliation(s)
- Shevon N Alexander
- Neuroimmunology and Behavior Laboratory, Department of Neuroscience, School of Behavioral and Brain Sciences, Center for Advanced Pain Studies, University of Texas at Dallas, 800 W. Campbell Road, BSB 10.537, Richardson, TX, 75080, USA
| | - Audrey R Green
- Neuroimmunology and Behavior Laboratory, Department of Neuroscience, School of Behavioral and Brain Sciences, Center for Advanced Pain Studies, University of Texas at Dallas, 800 W. Campbell Road, BSB 10.537, Richardson, TX, 75080, USA
| | - Emily K Debner
- Neuroimmunology and Behavior Laboratory, Department of Neuroscience, School of Behavioral and Brain Sciences, Center for Advanced Pain Studies, University of Texas at Dallas, 800 W. Campbell Road, BSB 10.537, Richardson, TX, 75080, USA
| | - Lindsey E Ramos Freitas
- Neuroimmunology and Behavior Laboratory, Department of Neuroscience, School of Behavioral and Brain Sciences, Center for Advanced Pain Studies, University of Texas at Dallas, 800 W. Campbell Road, BSB 10.537, Richardson, TX, 75080, USA
| | - Hanna M K Abdelhadi
- Neuroimmunology and Behavior Laboratory, Department of Neuroscience, School of Behavioral and Brain Sciences, Center for Advanced Pain Studies, University of Texas at Dallas, 800 W. Campbell Road, BSB 10.537, Richardson, TX, 75080, USA
| | - Thomas A Szabo-Pardi
- Neuroimmunology and Behavior Laboratory, Department of Neuroscience, School of Behavioral and Brain Sciences, Center for Advanced Pain Studies, University of Texas at Dallas, 800 W. Campbell Road, BSB 10.537, Richardson, TX, 75080, USA
| | - Michael D Burton
- Neuroimmunology and Behavior Laboratory, Department of Neuroscience, School of Behavioral and Brain Sciences, Center for Advanced Pain Studies, University of Texas at Dallas, 800 W. Campbell Road, BSB 10.537, Richardson, TX, 75080, USA.
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Sepulveda DE, Vrana KE, Kellogg JJ, Bisanz JE, Desai D, Graziane NM, Raup-Konsavage WM. The Potential of Cannabichromene (CBC) as a Therapeutic Agent. J Pharmacol Exp Ther 2024; 391:206-213. [PMID: 38777605 PMCID: PMC11493452 DOI: 10.1124/jpet.124.002166] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2024] [Revised: 04/04/2024] [Accepted: 04/24/2024] [Indexed: 05/25/2024] Open
Abstract
There is a growing interest in the use of medicinal plants to treat a variety of diseases, and one of the most commonly used medicinal plants globally is Cannabis sativa The two most abundant cannabinoids (Δ9-tetrahydrocannabinol and cannabidiol) have been governmentally approved to treat selected medical conditions; however, the plant produces over 100 cannabinoids, including cannabichromene (CBC). Although the cannabinoids share a common precursor molecule, cannabigerol, they are structurally and pharmacologically unique. These differences may engender differing therapeutic potentials. In this review, we will examine what is currently known about CBC with regards to pharmacodynamics, pharmacokinetics, and receptor profile. We will also discuss the therapeutic areas that have been examined for this cannabinoid, notably antinociceptive, antibacterial, and anti-seizure activities. Finally, we will discuss areas where new research is needed and potential novel medicinal applications for CBC. SIGNIFICANCE STATEMENT: Cannabichromene (CBC) has been suggested to have disparate therapeutic benefits such as anti-inflammatory, anticonvulsant, antibacterial, and antinociceptive effects. Most of the focus on the medical benefits of cannabinoids has been focused on Δ9-tetrahydrocannabinol and cannabidiol. The preliminary studies on CBC indicate that this phytocannabinoid may have unique therapeutic potential that warrants further investigation. Following easier access to hemp, CBC products are commercially available over-the-counter and are being widely utilized with little or no evidence of their safety or efficacy.
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Affiliation(s)
- Diana E Sepulveda
- Departments of Pharmacology (D.E.S., K.E.V., D.D., N.M.G., W.M.R.-K.) and Anesthesiology and Perioperative Medicine (D.E.S., N.M.G.), and Penn State Center for Cannabis & Natural Product Pharmaceutics (D.E.S., K.E.V., J.J.K., J.E.B., D.D., N.M.G., W.M.R.-K.), Penn State University College of Medicine, Hershey, Pennsylvania; and Departments of Veterinary and Biomedical Sciences (J.J.K.) and Biochemistry and Molecular Biology (J.E.B.), Pennsylvania State University, University Park, State College, Pennsylvania
| | - Kent E Vrana
- Departments of Pharmacology (D.E.S., K.E.V., D.D., N.M.G., W.M.R.-K.) and Anesthesiology and Perioperative Medicine (D.E.S., N.M.G.), and Penn State Center for Cannabis & Natural Product Pharmaceutics (D.E.S., K.E.V., J.J.K., J.E.B., D.D., N.M.G., W.M.R.-K.), Penn State University College of Medicine, Hershey, Pennsylvania; and Departments of Veterinary and Biomedical Sciences (J.J.K.) and Biochemistry and Molecular Biology (J.E.B.), Pennsylvania State University, University Park, State College, Pennsylvania
| | - Joshua J Kellogg
- Departments of Pharmacology (D.E.S., K.E.V., D.D., N.M.G., W.M.R.-K.) and Anesthesiology and Perioperative Medicine (D.E.S., N.M.G.), and Penn State Center for Cannabis & Natural Product Pharmaceutics (D.E.S., K.E.V., J.J.K., J.E.B., D.D., N.M.G., W.M.R.-K.), Penn State University College of Medicine, Hershey, Pennsylvania; and Departments of Veterinary and Biomedical Sciences (J.J.K.) and Biochemistry and Molecular Biology (J.E.B.), Pennsylvania State University, University Park, State College, Pennsylvania
| | - Jordan E Bisanz
- Departments of Pharmacology (D.E.S., K.E.V., D.D., N.M.G., W.M.R.-K.) and Anesthesiology and Perioperative Medicine (D.E.S., N.M.G.), and Penn State Center for Cannabis & Natural Product Pharmaceutics (D.E.S., K.E.V., J.J.K., J.E.B., D.D., N.M.G., W.M.R.-K.), Penn State University College of Medicine, Hershey, Pennsylvania; and Departments of Veterinary and Biomedical Sciences (J.J.K.) and Biochemistry and Molecular Biology (J.E.B.), Pennsylvania State University, University Park, State College, Pennsylvania
| | - Dhimant Desai
- Departments of Pharmacology (D.E.S., K.E.V., D.D., N.M.G., W.M.R.-K.) and Anesthesiology and Perioperative Medicine (D.E.S., N.M.G.), and Penn State Center for Cannabis & Natural Product Pharmaceutics (D.E.S., K.E.V., J.J.K., J.E.B., D.D., N.M.G., W.M.R.-K.), Penn State University College of Medicine, Hershey, Pennsylvania; and Departments of Veterinary and Biomedical Sciences (J.J.K.) and Biochemistry and Molecular Biology (J.E.B.), Pennsylvania State University, University Park, State College, Pennsylvania
| | - Nicholas M Graziane
- Departments of Pharmacology (D.E.S., K.E.V., D.D., N.M.G., W.M.R.-K.) and Anesthesiology and Perioperative Medicine (D.E.S., N.M.G.), and Penn State Center for Cannabis & Natural Product Pharmaceutics (D.E.S., K.E.V., J.J.K., J.E.B., D.D., N.M.G., W.M.R.-K.), Penn State University College of Medicine, Hershey, Pennsylvania; and Departments of Veterinary and Biomedical Sciences (J.J.K.) and Biochemistry and Molecular Biology (J.E.B.), Pennsylvania State University, University Park, State College, Pennsylvania
| | - Wesley M Raup-Konsavage
- Departments of Pharmacology (D.E.S., K.E.V., D.D., N.M.G., W.M.R.-K.) and Anesthesiology and Perioperative Medicine (D.E.S., N.M.G.), and Penn State Center for Cannabis & Natural Product Pharmaceutics (D.E.S., K.E.V., J.J.K., J.E.B., D.D., N.M.G., W.M.R.-K.), Penn State University College of Medicine, Hershey, Pennsylvania; and Departments of Veterinary and Biomedical Sciences (J.J.K.) and Biochemistry and Molecular Biology (J.E.B.), Pennsylvania State University, University Park, State College, Pennsylvania
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Turnbull J, Chapman V. Targeting the soluble epoxide hydrolase pathway as a novel therapeutic approach for the treatment of pain. Curr Opin Pharmacol 2024; 78:102477. [PMID: 39197248 DOI: 10.1016/j.coph.2024.102477] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2024] [Revised: 08/01/2024] [Accepted: 08/02/2024] [Indexed: 09/01/2024]
Abstract
Chronic pain is a major burden and the complexities of chronic pain pathophysiology, including both peripheral and central sensitisation mechanisms, involves multiple cell types (neuronal, immune, neuroimmune, and vascular) which substantially complicates the development of new effective analgesic treatments. The epoxy fatty acids (EpFAs), including the epoxyeicosatrienoic acids (EETs), are derived from the metabolism of polyunsaturated fatty acids (PUFAs) via the cytochrome P450 enzymatic pathway and act to shut-down inflammatory signalling and provide analgesia. The EpFAs are rapidly metabolised by the enzyme soluble epoxide hydrolase (sEH) into their corresponding diol metabolites, which recent studies suggest are pro-inflammatory and pro-nociceptive. This review discusses clinical and mechanistic evidence for targeting the sEH pathway for the treatment of pain.
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Affiliation(s)
- James Turnbull
- Pain Centre Versus Arthritis & NIHR Nottingham Biomedical Research Centre, School of Life Sciences, University of Nottingham, Nottingham, United Kingdom.
| | - Victoria Chapman
- Pain Centre Versus Arthritis & NIHR Nottingham Biomedical Research Centre, School of Life Sciences, University of Nottingham, Nottingham, United Kingdom
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9
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Humes C, Sic A, Knezevic NN. Substance P's Impact on Chronic Pain and Psychiatric Conditions-A Narrative Review. Int J Mol Sci 2024; 25:5905. [PMID: 38892091 PMCID: PMC11172719 DOI: 10.3390/ijms25115905] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2024] [Revised: 05/22/2024] [Accepted: 05/24/2024] [Indexed: 06/21/2024] Open
Abstract
Substance P (SP) plays a crucial role in pain modulation, with significant implications for major depressive disorder (MDD), anxiety disorders, and post-traumatic stress disorder (PTSD). Elevated SP levels are linked to heightened pain sensitivity and various psychiatric conditions, spurring interest in potential therapeutic interventions. In chronic pain, commonly associated with MDD and anxiety disorders, SP emerges as a key mediator in pain and emotional regulation. This review examines SP's impact on pain perception and its contributions to MDD, anxiety disorders, and PTSD. The association of SP with increased pain sensitivity and chronic pain conditions underscores its importance in pain modulation. Additionally, SP influences the pathophysiology of MDD, anxiety disorders, and PTSD, highlighting its potential as a therapeutic target. Understanding SP's diverse effects provides valuable insights into the mechanisms underlying these psychiatric disorders and their treatment. Further research is essential to explore SP modulation in psychiatric disorders and develop more effective treatment strategies.
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Affiliation(s)
- Charles Humes
- Department of Anesthesiology, Advocate Illinois Masonic Medical Center, Chicago, IL 60657, USA; (C.H.); (A.S.)
- Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064, USA
| | - Aleksandar Sic
- Department of Anesthesiology, Advocate Illinois Masonic Medical Center, Chicago, IL 60657, USA; (C.H.); (A.S.)
- Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia
| | - Nebojsa Nick Knezevic
- Department of Anesthesiology, Advocate Illinois Masonic Medical Center, Chicago, IL 60657, USA; (C.H.); (A.S.)
- Department of Anesthesiology, University of Illinois, Chicago, IL 60612, USA
- Department of Surgery, University of Illinois, Chicago, IL 60612, USA
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10
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Stasiłowicz-Krzemień A, Nogalska W, Maszewska Z, Maleszka M, Dobroń M, Szary A, Kępa A, Żarowski M, Hojan K, Lukowicz M, Cielecka-Piontek J. The Use of Compounds Derived from Cannabis sativa in the Treatment of Epilepsy, Painful Conditions, and Neuropsychiatric and Neurodegenerative Disorders. Int J Mol Sci 2024; 25:5749. [PMID: 38891938 PMCID: PMC11171823 DOI: 10.3390/ijms25115749] [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: 03/12/2024] [Revised: 05/20/2024] [Accepted: 05/23/2024] [Indexed: 06/21/2024] Open
Abstract
Neurological disorders present a wide range of symptoms and challenges in diagnosis and treatment. Cannabis sativa, with its diverse chemical composition, offers potential therapeutic benefits due to its anticonvulsive, analgesic, anti-inflammatory, and neuroprotective properties. Beyond cannabinoids, cannabis contains terpenes and polyphenols, which synergistically enhance its pharmacological effects. Various administration routes, including vaporization, oral ingestion, sublingual, and rectal, provide flexibility in treatment delivery. This review shows the therapeutic efficacy of cannabis in managing neurological disorders such as epilepsy, neurodegenerative diseases, neurodevelopmental disorders, psychiatric disorders, and painful pathologies. Drawing from surveys, patient studies, and clinical trials, it highlights the potential of cannabis in alleviating symptoms, slowing disease progression, and improving overall quality of life for patients. Understanding the diverse therapeutic mechanisms of cannabis can open up possibilities for using this plant for individual patient needs.
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Affiliation(s)
- Anna Stasiłowicz-Krzemień
- Department of Pharmacognosy and Biomaterials, Faculty of Pharmacy, Poznan University of Medical Sciences, Rokietnicka 3, 60-806 Poznan, Poland; (A.S.-K.)
| | - Wiktoria Nogalska
- Department of Pharmacognosy and Biomaterials, Faculty of Pharmacy, Poznan University of Medical Sciences, Rokietnicka 3, 60-806 Poznan, Poland; (A.S.-K.)
| | - Zofia Maszewska
- Department of Pharmacognosy and Biomaterials, Faculty of Pharmacy, Poznan University of Medical Sciences, Rokietnicka 3, 60-806 Poznan, Poland; (A.S.-K.)
| | - Mateusz Maleszka
- Department of Pharmacognosy and Biomaterials, Faculty of Pharmacy, Poznan University of Medical Sciences, Rokietnicka 3, 60-806 Poznan, Poland; (A.S.-K.)
| | - Maria Dobroń
- Department of Pharmacognosy and Biomaterials, Faculty of Pharmacy, Poznan University of Medical Sciences, Rokietnicka 3, 60-806 Poznan, Poland; (A.S.-K.)
| | - Agnieszka Szary
- Department of Pharmacognosy and Biomaterials, Faculty of Pharmacy, Poznan University of Medical Sciences, Rokietnicka 3, 60-806 Poznan, Poland; (A.S.-K.)
| | - Aleksandra Kępa
- Department of Pharmacognosy and Biomaterials, Faculty of Pharmacy, Poznan University of Medical Sciences, Rokietnicka 3, 60-806 Poznan, Poland; (A.S.-K.)
| | - Marcin Żarowski
- Department of Developmental Neurology, Poznan University of Medical Sciences, Przybyszewski 49, 60-355 Poznan, Poland;
| | - Katarzyna Hojan
- Department of Occupational Therapy, Poznan University of Medical Sciences, Swięcickiego 6, 61-847 Poznan, Poland;
- Department of Rehabilitation, Greater Poland Cancer Centre, Garbary 15, 61-866 Poznan, Poland
| | - Malgorzata Lukowicz
- Department of Rehabilitation, Centre of Postgraduate Medical Education, Konarskiego 13, 05-400 Otwock, Poland;
| | - Judyta Cielecka-Piontek
- Department of Pharmacognosy and Biomaterials, Faculty of Pharmacy, Poznan University of Medical Sciences, Rokietnicka 3, 60-806 Poznan, Poland; (A.S.-K.)
- Department of Pharmacology and Phytochemistry, Institute of Natural Fibres and Medicinal Plants, Wojska Polskiego 71b, 60-630 Poznan, Poland
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11
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Reza ASMA, Raihan R, Azam S, Shahanewz M, Nasrin MS, Siddique MAB, Uddin MN, Dey AK, Sadik MG, Alam AK. Experimental and pharmacoinformatic approaches unveil the neuropharmacological and analgesic potential of chloroform fraction of Roktoshirinchi (Achyranthes ferruginea Roxb.). JOURNAL OF ETHNOPHARMACOLOGY 2024; 324:117769. [PMID: 38219886 DOI: 10.1016/j.jep.2024.117769] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/29/2023] [Revised: 01/07/2024] [Accepted: 01/11/2024] [Indexed: 01/16/2024]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Achyranthes ferruginea (A. ferruginea) Roxb. is a common plant used in traditional medicine in Asia and Africa. It has a variety of local names, including "Gulmanci" in Nigeria, "Dangar" in Pakistan, "Thola" in Ethiopia, and "Roktoshirinchi" in Bangladesh. It is edible and has several ethnomedical uses for a wide range of illnesses, including hysteria, dropsy, constipation, piles, boils, asthma, and shigellosis. However, the neuropharmacological and analgesic potential of A. ferruginea remains uninvestigated. AIM OF THE STUDY To assess the neuropharmacological and analgesic potential of A. ferruginea through a multifaceted approach encompassing both experimental and computational models. MATERIALS AND METHODS Methanol was used to extract the leaves of A. ferruginea. It was then fractionated with low to high polar solvents (n-hexane, chloroform, ethyl acetate, and water) to get different fractions, including chloroform fraction (CLF). The study selected CLF at different doses and conducted advanced chemical element and proximate analyses, as well as phytochemical profiling using GC-MS. Toxicological studies were done at 300 μg per rat per day for 14 days. Cholinesterase inhibitory potential was checked using an in-vitro colorimetric assay. Acetic acid-induced writhing (AAWT) and formalin-induced licking tests (FILT) were used to assess anti-nociceptive effects. The forced swim test (FST), tail suspension test (TST), elevated plus maze (EPM), hole board test (HBT), and light and dark box test (LDB) were among the behavioral tests used to assess depression and anxiolytic activity. Network pharmacology-based analysis was performed on selected compounds using the search tool for interacting chemicals-5 (STITCH 5), Swiss target prediction tool, and search tool for the retrieval of interacting genes and proteins (STRING) database to link their role with genes involved in neurological disorders through gene ontology and reactome analysis. RESULTS Qualitative chemical element analysis revealed the presence of 15 elements, including Na, K, Ca, Mg, P, and Zn. The moisture content, ash value, and organic matter were found to be 11.12, 11.03, and 88.97%, respectively. GC-MS data revealed that the CLF possesses 25 phytoconstituents. Toxicological studies suggested the CLF has no effects on normal growth, hematological and biochemical parameters, or cellular organs after 14 days at 300 μg per rat. The CLF markedly reduced the activity of both acetylcholinesterase and butyrylcholinesterase (IC50: 56.22 and 13.22 μg/mL, respectively). Promising dose-dependent analgesic activity (p < 0.05) was observed in chemically-induced pain models. The TST and FST showed a dose-dependent substantial reduction in immobility time due to the CLF. Treatment with CLF notably increased the number of open arm entries and time spent in the EPM test at doses of 200 and 400 mg/kg b.w. The CLF showed significant anxiolytic activity at 200 mg/kg b.w. in the HBT test, whereas a similar activity was observed at 400 mg/kg b.w. in the EPM test. A notable increase in the amount of time spent in the light compartment was observed in the LDB test by mice treated with CLF, suggesting an anxiolytic effect. A network pharmacology study demonstrated the relationship between the phytochemicals and a number of targets, such as PPARA, PPARG, CHRM1, and HTR2, which are connected to the shown bioactivities. CONCLUSIONS This study demonstrated the safety of A. ferruginea and its efficacy in attenuating cholinesterase inhibitory activity, central and peripheral pain, anxiety, and depression, warranting further exploration of its therapeutic potential.
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Affiliation(s)
- A S M Ali Reza
- Department of Pharmacy, International Islamic University Chittagong, Chittagong, 4318, Bangladesh.
| | - Riaj Raihan
- Department of Pharmacy, International Islamic University Chittagong, Chittagong, 4318, Bangladesh.
| | - Saidul Azam
- Department of Pharmacy, International Islamic University Chittagong, Chittagong, 4318, Bangladesh.
| | - Mohammed Shahanewz
- Department of Pharmacy, International Islamic University Chittagong, Chittagong, 4318, Bangladesh.
| | - Mst Samima Nasrin
- Department of Pharmacy, International Islamic University Chittagong, Chittagong, 4318, Bangladesh.
| | - Md Abu Bakar Siddique
- Institute of National Analytical Research and Service (INARS), Bangladesh Council of Scientific and Industrial Research (BCSIR), Dhanmondi, Dhaka, 1205, Bangladesh.
| | - Md Nazim Uddin
- Institute of Food Science and Technology (IFST), Bangladesh Council of Scientific and Industrial Research (BCSIR), Dhanmondi, Dhaka, 1205, Bangladesh.
| | - Anik Kumar Dey
- Department of Pharmacy, University of Rajshahi, Rajshahi, 6205, Bangladesh.
| | - Md Golam Sadik
- Department of Pharmacy, University of Rajshahi, Rajshahi, 6205, Bangladesh.
| | - Ahm Khurshid Alam
- Department of Pharmacy, University of Rajshahi, Rajshahi, 6205, Bangladesh.
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12
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Bu Y, Yang S, Wang D, Hu S, Zhang Q, Wu Z, Yang C. Role of soluble epoxide hydrolase in pain and depression comorbidity. Neurobiol Dis 2024; 193:106443. [PMID: 38395315 DOI: 10.1016/j.nbd.2024.106443] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Revised: 02/15/2024] [Accepted: 02/19/2024] [Indexed: 02/25/2024] Open
Abstract
The coexistence of chronic pain and depression in clinical practice places a substantial social burden and profoundly impacts in patients. Although a clear correlation exists, the underlying mechanism of comorbidity between chronic pain and depression remains elusive. Research conducted in recent decades has uncovered that soluble epoxide hydrolase, a pivotal enzyme in the metabolism of polyunsaturated fatty acids, plays a crucial role in inflammation. Interestingly, this enzyme is intricately linked to the development of both pain and depression. With this understanding, this review aims to summarize the roles of soluble epoxide hydrolase in pain, depression, and their comorbidity. Simultaneously, we will also explore the underlying mechanisms, providing guidance for future research and drug development.
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Affiliation(s)
- Yuchen Bu
- Department of Anesthesiology and Perioperative Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Siqi Yang
- Department of Anesthesiology and Perioperative Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Di Wang
- Department of Anesthesiology and Perioperative Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Suwan Hu
- Department of Anesthesiology and Perioperative Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Qi Zhang
- Department of Anesthesiology and Perioperative Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Zifeng Wu
- Department of Anesthesiology and Perioperative Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
| | - Chun Yang
- Department of Anesthesiology and Perioperative Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
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13
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Benvenutti L, Wolff FR, Corrêa TP, Melato J, Goldoni FC, De Faveri R, Patel YBK, de Souza JA, Grockoski HA, Nilz PM, Bombardelli CL, Remor AP, Varela KG, Costa NTC, Hernandes MZ, Lacerda MG, Rodrigues KD, Milton FA, Neves FDAR, Pereira MES, Kormann Imianowsky EC, de Campos Buzzi F, Brunaldi Marutani VH, Stoeberl LC, Correa R, Eller S, de Oliveira TF, Gonçalves TBP, da Silva RC, Passos GF, da Costa R, Santin JR, Quintão NLM. A partial agonist of PPARγ prevents paclitaxel-induced peripheral neuropathy in mice, by inhibiting neuroinflammation. Br J Pharmacol 2024; 181:1128-1149. [PMID: 37721089 DOI: 10.1111/bph.16244] [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: 01/04/2023] [Revised: 09/07/2023] [Accepted: 09/07/2023] [Indexed: 09/19/2023] Open
Abstract
BACKGROUND AND PURPOSE Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect of paclitaxel, affecting 30-50% of patients. Increased survival and concern with patients' quality of life have encouraged the search for new tools to prevent paclitaxel-induced neuropathy. This study presents the glitazone 4-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]-N-phenylbenzene-sulfonamide (TZD-A1) as a partial agonist of peroxisome proliferator-activated receptor γ (PPARγ), its toxicological profile and effects on paclitaxel-induced CIPN in mice. EXPERIMENTAL APPROACH Interactions of TZD-A1 with PPARγ were analysed using in silico docking and in vitro reporter gene assays. Pharmacokinetics and toxicity were evaluated using in silico, in vitro and in vivo (C57Bl/6 mice) analyses. Effects of TZD-A1 on CIPN were investigated in paclitaxel-injected mice. Axonal and dorsal root ganglion damage, mitochondrial complex activity and cytokine levels, brain-derived neurotrophic factor (BDNF), nuclear factor erythroid 2-related factor 2 (Nrf2) and PPARγ, were also measured. KEY RESULTS Docking analysis predicted TZD-A1 interactions with PPARγ compatible with partial agonism, which were corroborated by in vitro reporter gene assays. Good oral bioavailability and safety profile of TZD-A1 were shown in silico, in vitro and in vivo. Paclitaxel-injected mice, concomitantly treated with TZD-A1 by i.p. or oral administration, exhibited decreased mechanical and thermal hypersensitivity, effects apparently mediated by inhibition of neuroinflammation and mitochondrial damage, through increasing Nrf2 and PPARγ levels, and up-regulating BDNF. CONCLUSION AND IMPLICATIONS TZD-A1, a partial agonist of PPARγ, provided neuroprotection and reduced hypersensitivity induced by paclitaxel. Allied to its safety profile and good bioavailability, TZD-A1 is a promising drug candidate to prevent and treat CIPN in cancer patients.
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Affiliation(s)
- Larissa Benvenutti
- Postgraduate Program in Pharmaceutical Science, Universidade do Vale do Itajaí (UNIVALI), Itajaí, Santa Catarina, Brazil
| | - Fellippe Ramos Wolff
- Postgraduate Program in Pharmaceutical Science, Universidade do Vale do Itajaí (UNIVALI), Itajaí, Santa Catarina, Brazil
| | - Thiago Patrício Corrêa
- Postgraduate Program in Pharmaceutical Science, Universidade do Vale do Itajaí (UNIVALI), Itajaí, Santa Catarina, Brazil
| | - Jessica Melato
- Postgraduate Program in Pharmaceutical Science, Universidade do Vale do Itajaí (UNIVALI), Itajaí, Santa Catarina, Brazil
| | - Fernanda Capitanio Goldoni
- Postgraduate Program in Pharmaceutical Science, Universidade do Vale do Itajaí (UNIVALI), Itajaí, Santa Catarina, Brazil
| | - Renata De Faveri
- Postgraduate Program in Pharmaceutical Science, Universidade do Vale do Itajaí (UNIVALI), Itajaí, Santa Catarina, Brazil
| | - Yasmin Beatrisse Klein Patel
- Biomedicine, School of Health Sciences, Universidade do Vale do Itajaí (UNIVALI), Itajaí, Santa Catarina, Brazil
| | - Jade André de Souza
- Biomedicine, School of Health Sciences, Universidade do Vale do Itajaí (UNIVALI), Itajaí, Santa Catarina, Brazil
| | - Heloise Adeli Grockoski
- Biomedicine, School of Health Sciences, Universidade do Vale do Itajaí (UNIVALI), Itajaí, Santa Catarina, Brazil
| | - Paulo Mateus Nilz
- Pharmacy Courses, School of Health Sciences, Universidade do Vale do Itajaí (UNIVALI), Itajaí, Santa Catarina, Brazil
| | - Cleber Luiz Bombardelli
- Postgraduate Program in Pharmaceutical Science, Universidade do Vale do Itajaí (UNIVALI), Itajaí, Santa Catarina, Brazil
| | - Aline Pertile Remor
- Postgraduate Program in Bioscience and Health, Universidade do Oeste de Santa Catarina (UNOESC), Joaçaba, Santa Catarina, Brazil
| | - Karina Giacomini Varela
- Postgraduate Program in Bioscience and Health, Universidade do Oeste de Santa Catarina (UNOESC), Joaçaba, Santa Catarina, Brazil
| | - Natáli Tereza Capistrano Costa
- Laboratório de Química Teórica e Medicinal (LQTM), Departamento de Ciências Farmacêuticas, Universidade Federal de Pernambuco (UFPE), Recife, Pernambuco, Brazil
| | - Marcelo Zaldini Hernandes
- Laboratório de Química Teórica e Medicinal (LQTM), Departamento de Ciências Farmacêuticas, Universidade Federal de Pernambuco (UFPE), Recife, Pernambuco, Brazil
| | - Mariella Guimarães Lacerda
- Laboratory of Molecular Pharmacology, Faculty of Health Sciences, University of Brasilia (UnB), Brasília, Distrito Federal, Brazil
| | - Kathlen Deruci Rodrigues
- Laboratory of Molecular Pharmacology, Faculty of Health Sciences, University of Brasilia (UnB), Brasília, Distrito Federal, Brazil
| | - Flora Aparecida Milton
- Laboratory of Molecular Pharmacology, Faculty of Health Sciences, University of Brasilia (UnB), Brasília, Distrito Federal, Brazil
| | - Francisco de Assis Rocha Neves
- Laboratory of Molecular Pharmacology, Faculty of Health Sciences, University of Brasilia (UnB), Brasília, Distrito Federal, Brazil
| | | | | | - Fátima de Campos Buzzi
- Postgraduate Program in Pharmaceutical Science, Universidade do Vale do Itajaí (UNIVALI), Itajaí, Santa Catarina, Brazil
| | - Victor Hugo Brunaldi Marutani
- Laboratory of Animal Pathology, Department of Preventive Veterinary Medicine, Universidade Estadual de Londrina (UEL), Londrina, Paraná, Brazil
| | - Luis Carlos Stoeberl
- Postgraduate Program in Pharmaceutical Science, Universidade do Vale do Itajaí (UNIVALI), Itajaí, Santa Catarina, Brazil
| | - Rogério Correa
- Postgraduate Program in Pharmaceutical Science, Universidade do Vale do Itajaí (UNIVALI), Itajaí, Santa Catarina, Brazil
| | - Sarah Eller
- Graduate Program in Health Sciences, Federal University of Health Sciences of Porto Alegre (UFCSPA), Porto Alegre, Rio Grande do Sul, Brazil
| | - Tiago Franco de Oliveira
- Graduate Program in Health Sciences, Federal University of Health Sciences of Porto Alegre (UFCSPA), Porto Alegre, Rio Grande do Sul, Brazil
| | | | - Raquel Costa da Silva
- School of Pharmacy, Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro, Rio de Janeiro, Brazil
| | - Giselle Fazzioni Passos
- School of Pharmacy, Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro, Rio de Janeiro, Brazil
| | - Robson da Costa
- School of Pharmacy, Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro, Rio de Janeiro, Brazil
| | - José Roberto Santin
- Postgraduate Program in Pharmaceutical Science, Universidade do Vale do Itajaí (UNIVALI), Itajaí, Santa Catarina, Brazil
| | - Nara Lins Meira Quintão
- Postgraduate Program in Pharmaceutical Science, Universidade do Vale do Itajaí (UNIVALI), Itajaí, Santa Catarina, Brazil
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14
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Tang Y, Du J, Wu H, Wang M, Liu S, Tao F. Potential Therapeutic Effects of Short-Chain Fatty Acids on Chronic Pain. Curr Neuropharmacol 2024; 22:191-203. [PMID: 36173071 PMCID: PMC10788890 DOI: 10.2174/1570159x20666220927092016] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Revised: 07/03/2022] [Accepted: 09/13/2022] [Indexed: 11/22/2022] Open
Abstract
The intestinal homeostasis maintained by the gut microbiome and relevant metabolites is essential for health, and its disturbance leads to various intestinal or extraintestinal diseases. Recent studies suggest that gut microbiome-derived metabolites short-chain fatty acids (SCFAs) are involved in different neurological disorders (such as chronic pain). SCFAs are produced by bacterial fermentation of dietary fibers in the gut and contribute to multiple host processes, including gastrointestinal regulation, cardiovascular modulation, and neuroendocrine-immune homeostasis. Although SCFAs have been implicated in the modulation of chronic pain, the detailed mechanisms that underlie such roles of SCFAs remain to be further investigated. In this review, we summarize currently available research data regarding SCFAs as a potential therapeutic target for chronic pain treatment and discuss several possible mechanisms by which SCFAs modulate chronic pain.
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Affiliation(s)
- Yuanyuan Tang
- School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, Henan, China
- Key Laboratory for Molecular Neurology of Xinxiang, Xinxiang, Henan, China
| | - Juan Du
- School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, Henan, China
| | - Hongfeng Wu
- School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, Henan, China
| | - Mengyao Wang
- School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, Henan, China
| | - Sufang Liu
- Department of Biomedical Sciences, College of Dentistry, Texas A&M University Dallas, Texas, USA
| | - Feng Tao
- Department of Biomedical Sciences, College of Dentistry, Texas A&M University Dallas, Texas, USA
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15
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Sullere S, Kunczt A, McGehee DS. A cholinergic circuit that relieves pain despite opioid tolerance. Neuron 2023; 111:3414-3434.e15. [PMID: 37734381 PMCID: PMC10843525 DOI: 10.1016/j.neuron.2023.08.017] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Revised: 04/19/2023] [Accepted: 08/16/2023] [Indexed: 09/23/2023]
Abstract
Chronic pain is a tremendous burden for afflicted individuals and society. Although opioids effectively relieve pain, significant adverse outcomes limit their utility and efficacy. To investigate alternate pain control mechanisms, we explored cholinergic signaling in the ventrolateral periaqueductal gray (vlPAG), a critical nexus for descending pain modulation. Biosensor assays revealed that pain states decreased acetylcholine release in vlPAG. Activation of cholinergic projections from the pedunculopontine tegmentum to vlPAG relieved pain, even in opioid-tolerant conditions, through ⍺7 nicotinic acetylcholine receptors (nAChRs). Activating ⍺7 nAChRs with agonists or stimulating endogenous acetylcholine inhibited vlPAG neuronal activity through Ca2+ and peroxisome proliferator-activated receptor α (PPAR⍺)-dependent signaling. In vivo 2-photon imaging revealed that chronic pain induces aberrant excitability of vlPAG neuronal ensembles and that ⍺7 nAChR-mediated inhibition of these cells relieves pain, even after opioid tolerance. Finally, pain relief through these cholinergic mechanisms was not associated with tolerance, reward, or withdrawal symptoms, highlighting its potential clinical relevance.
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Affiliation(s)
- Shivang Sullere
- Committee on Neurobiology, University of Chicago, Chicago, IL 60637, USA
| | - Alissa Kunczt
- Department of Anesthesia and Critical Care, University of Chicago, Chicago, IL 60637, USA
| | - Daniel S McGehee
- Committee on Neurobiology, University of Chicago, Chicago, IL 60637, USA; Department of Anesthesia and Critical Care, University of Chicago, Chicago, IL 60637, USA.
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16
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Hempel B, Crissman M, Pari S, Klein B, Bi GH, Alton H, Xi ZX. PPARα and PPARγ are expressed in midbrain dopamine neurons and modulate dopamine- and cannabinoid-mediated behavior in mice. Mol Psychiatry 2023; 28:4203-4214. [PMID: 37479780 PMCID: PMC10799974 DOI: 10.1038/s41380-023-02182-0] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2023] [Revised: 07/03/2023] [Accepted: 07/05/2023] [Indexed: 07/23/2023]
Abstract
Peroxisome proliferator-activated receptors (PPARs) are a family of nuclear receptors that regulate gene expression. Δ9-tetrahydrocannabinol (Δ9-THC) is a PPARγ agonist and some endocannabinoids are natural activators of PPARα and PPARγ. However, little is known regarding their cellular distributions in the brain and functional roles in cannabinoid action. Here, we first used RNAscope in situ hybridization and immunohistochemistry assays to examine the cellular distributions of PPARα and PPARγ expression in the mouse brain. We found that PPARα and PPARγ are expressed in ~70% of midbrain dopamine (DA) neurons. In the amygdala, PPARα is expressed in ~60% of glutamatergic neurons, while PPARγ is expressed in ~60% of GABA neurons. However, no PPARα/γ signal was detected in GABA neurons in the nucleus accumbens. We then used a series of behavioral assays to determine the functional roles of PPARα/γ in the CNS effects of Δ9-THC. We found that optogenetic stimulation of midbrain DA neurons was rewarding as assessed by optical intracranial self-stimulation (oICSS) in DAT-cre mice. Δ9-THC and a PPARγ (but not PPARα) agonist dose-dependently inhibited oICSS. Pretreatment with PPARα or PPARγ antagonists attenuated the Δ9-THC-induced reduction in oICSS and Δ9-THC-induced anxiogenic effects. In addition, a PPARγ agonist increased, while PPARα or PPARγ antagonists decreased open-field locomotion. Pretreatment with PPARα or PPARγ antagonists potentiated Δ9-THC-induced hypoactivity and catalepsy but failed to alter Δ9-THC-induced analgesia, hypothermia and immobility. These findings provide the first anatomical and functional evidence supporting an important role of PPARα/γ in DA-dependent behavior and cannabinoid action.
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Affiliation(s)
- Briana Hempel
- Addiction Biology Unit, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse, Intramural Research Program, Baltimore, MD, USA
- Medication Development Program, National Institute on Drug Abuse, Intramural Research Program, Baltimore, MD, USA
| | - Madeline Crissman
- Neuropsychopharmacology Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse, Intramural Research Program, Baltimore, MD, USA
| | - Sruti Pari
- Neuropsychopharmacology Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse, Intramural Research Program, Baltimore, MD, USA
| | - Benjamin Klein
- Addiction Biology Unit, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse, Intramural Research Program, Baltimore, MD, USA
- Medication Development Program, National Institute on Drug Abuse, Intramural Research Program, Baltimore, MD, USA
| | - Guo-Hua Bi
- Addiction Biology Unit, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse, Intramural Research Program, Baltimore, MD, USA
- Medication Development Program, National Institute on Drug Abuse, Intramural Research Program, Baltimore, MD, USA
| | - Hannah Alton
- Addiction Biology Unit, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse, Intramural Research Program, Baltimore, MD, USA
- Medication Development Program, National Institute on Drug Abuse, Intramural Research Program, Baltimore, MD, USA
| | - Zheng-Xiong Xi
- Addiction Biology Unit, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse, Intramural Research Program, Baltimore, MD, USA.
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17
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Déciga-Campos M, Jaramillo-Morales OA, Espinosa-Juárez JV, Aguilera-Martínez ME, Ventura-Martínez R, López-Muñoz FJ. N-palmitoylethanolamide synergizes the antinociception of morphine and gabapentin in the formalin test in mice. J Pharm Pharmacol 2023; 75:1154-1162. [PMID: 36905375 DOI: 10.1093/jpp/rgad004] [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: 07/04/2022] [Accepted: 01/19/2023] [Indexed: 03/12/2023]
Abstract
OBJECTIVE The antinociceptive pharmacological interaction between N-palmitoylethanolamide (PEA) and morphine (MOR), as well as gabapentin (GBP), was investigated to obtain synergistic antinociception at doses where side effects were minimal. In addition, the possible antinociceptive mechanism of PEA + MOR or PEA + GBP combinations was explored. METHODS Individual dose-response curves (DRCs) of PEA, MOR and GBP were evaluated in female mice in which intraplantar nociception was induced with 2% formalin. Isobolographic method was used to detect the pharmacological interaction in the combination of PEA + MOR or PEA + GBP. KEY FINDINGS The ED50 was calculated from the DRC; the order of potency was MOR > PEA > GBP. The isobolographic analysis was obtained at a 1:1 ratio to determine the pharmacological interaction. The experimental values of flinching (PEA + MOR, Zexp = 2.72 ± 0.2 μg/paw and PEA + GBP Zexp = 2.77 ± 0.19 μg/paw) were significantly lower than those calculated theoretically (PEA + MOR Zadd = 7.78 ± 1.07 and PEA + GBP Zadd = 24.05 ± 1.91 μg/paw), resulting in synergistic antinociception. Pretreatment with GW6471 and naloxone demonstrated that peroxisome proliferator-activated receptor alpha (PPARα) and opioid receptors are involved in both interactions. CONCLUSIONS These results suggest that MOR and GBP synergistically enhance PEA-induced antinociception through PPARα and opioid receptor mechanisms. Furthermore, the results suggest that combinations containing PEA with MOR or GBP could be of interest in aiding the treatment of inflammatory pain.
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Affiliation(s)
- Myrna Déciga-Campos
- Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, México, México
| | - Osmar Antonio Jaramillo-Morales
- Departamento de Enfermería y Obstetricia, División de Ciencias de la Vida, Campus Irapuato-Salamanca, Universidad de Guanajuato, Irapuato, Guanajuato, México
| | | | - María Elena Aguilera-Martínez
- Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, México, México
| | - Rosa Ventura-Martínez
- Departamento de Farmacología, Facultad de Medicina, Universidad Nacional Autónoma de México, Delegación Coyoacán, México, México
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18
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Xi ZX, Hempel B, Crissman M, Pari S, Klein B, Bi GH, Alton H. PPARα and PPARγ are expressed in midbrain dopamine neurons and modulate dopamine- and cannabinoid-mediated behavior in mice. RESEARCH SQUARE 2023:rs.3.rs-2614714. [PMID: 36909477 PMCID: PMC10002816 DOI: 10.21203/rs.3.rs-2614714/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/06/2023]
Abstract
Peroxisome proliferator-activated receptors (PPARs) are a family of nuclear receptors that regulate gene expression. Δ 9 -tetrahydrocannabinol (Δ 9 -THC) is a PPARg agonist and some endocannabinoids are natural activators of PPAR a and PPARg. Therefore, both the receptors are putative cannabinoid receptors. However, little is known regarding their cellular distributions in the brain and functional roles in cannabinoid action. Here we first used RNAscope in situ hybridization and immunohistochemistry assays to examine the cellular distributions of PPARα and PPARγ expression in the mouse brain. We found that PPARα and PPARγ are highly expressed in ~70% midbrain dopamine (DA) neurons and in ~50% GABAergic and ~50% glutamatergic neurons in the amygdala. However, no PPARα/γ signal was detected in GABAergic neurons in the nucleus accumbens. We then used a series of behavioral assays to determine the functional roles of PPARα/γ in the CNS effects of Δ 9 -THC. We found that optogenetic stimulation of midbrain DA neurons was rewarding as assessed by optical intracranial self-stimulation (oICSS) in DAT-cre mice. Δ 9 -THC and a PPARγ (but not PPARα) agonist dose-dependently inhibited oICSS, suggesting that dopaminergic PPARγ modulates DA-dependent behavior. Surprisingly, pretreatment with PPARα or PPARγ antagonists dose-dependently attenuated the Δ 9 -THC-induced reduction in oICSS and anxiogenic effects. In addition, a PPARγ agonist increased, while PPARa or PPARγ antagonists decreased open-field locomotion. Pretreatment with PPARa or PPARγ antagonists potentiated Δ 9 -THC-induced hypoactivity and catalepsy but failed to alter Δ 9 -THC-induced analgesia, hypothermia and immobility. These findings provide the first anatomical and functional evidence supporting an important role of PPARa/g in DA-dependent behavior and cannabinoid action.
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Aretxabala X, García del Caño G, Barrondo S, López de Jesús M, González-Burguera I, Saumell-Esnaola M, Goicolea MA, Sallés J. Endocannabinoid 2-Arachidonoylglycerol Synthesis and Metabolism at Neuronal Nuclear Matrix Fractions Derived from Adult Rat Brain Cortex. Int J Mol Sci 2023; 24:ijms24043165. [PMID: 36834575 PMCID: PMC9965625 DOI: 10.3390/ijms24043165] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Revised: 01/27/2023] [Accepted: 02/02/2023] [Indexed: 02/08/2023] Open
Abstract
In this report, we describe the kinetics characteristics of the diacylglycerol lipase-α (DGLα) located at the nuclear matrix of nuclei derived from adult cortical neurons. Thus, using high-resolution fluorescence microscopy, classical biochemical subcellular fractionation, and Western blot techniques, we demonstrate that the DGLα enzyme is located in the matrix of neuronal nuclei. Furthermore, by quantifying the 2-arachidonoylglycerol (2-AG) level by liquid chromatography and mass spectrometry when 1-stearoyl-2-arachidonoyl-sn-glycerol (SAG) was exogenously added as substrate, we describe the presence of a mechanism for 2-AG production through DGLα dependent biosynthesis with an apparent Km (Kmapp) of 180 µM and a Vmax of 1.3 pmol min-1 µg-1 protein. We also examined the presence of enzymes with hydrolytic and oxygenase activities that are able to use 2-AG as substrate, and described the localization and compartmentalization of the major 2-AG degradation enzymes, namely monoacylglycerol lipase (MGL), fatty acid amide hydrolase (FAAH), α/β-hydrolase domain 12 protein (ABHD12) and cyclooxygenase-2 (COX2). Of these, only ABHD12 exhibited the same distribution with respect to chromatin, lamin B1, SC-35 and NeuN as that described for DGLα. When 2-AG was exogenously added, we observed the production of arachidonic acid (AA), which was prevented by inhibitors (but not specific MGL or ABHD6 inhibitors) of the ABHD family. Overall, our results expand knowledge about the subcellular distribution of neuronal DGLα, and provide biochemical and morphological evidence to ensure that 2-AG is produced in the neuronal nuclear matrix. Thus, this work paves the way for proposing a working hypothesis about the role of 2-AG produced in neuronal nuclei.
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Affiliation(s)
- Xabier Aretxabala
- Department of Neurosciences, Faculty of Pharmacy, University of the Basque Country (UPV/EHU), 01006 Vitoria-Gasteiz, Spain
| | - Gontzal García del Caño
- Department of Neurosciences, Faculty of Pharmacy, University of the Basque Country (UPV/EHU), 01006 Vitoria-Gasteiz, Spain
- Bioaraba, Neurofarmacología Celular y Molecular, 01008 Vitoria-Gasteiz, Spain
| | - Sergio Barrondo
- Bioaraba, Neurofarmacología Celular y Molecular, 01008 Vitoria-Gasteiz, Spain
- Department of Pharmacology, Faculty of Pharmacy, University of the Basque Country (UPV/EHU), 01006 Vitoria-Gasteiz, Spain
- Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), 28029 Madrid, Spain
| | - Maider López de Jesús
- Bioaraba, Neurofarmacología Celular y Molecular, 01008 Vitoria-Gasteiz, Spain
- Department of Pharmacology, Faculty of Pharmacy, University of the Basque Country (UPV/EHU), 01006 Vitoria-Gasteiz, Spain
| | - Imanol González-Burguera
- Department of Neurosciences, Faculty of Pharmacy, University of the Basque Country (UPV/EHU), 01006 Vitoria-Gasteiz, Spain
- Bioaraba, Neurofarmacología Celular y Molecular, 01008 Vitoria-Gasteiz, Spain
| | - Miquel Saumell-Esnaola
- Bioaraba, Neurofarmacología Celular y Molecular, 01008 Vitoria-Gasteiz, Spain
- Department of Pharmacology, Faculty of Pharmacy, University of the Basque Country (UPV/EHU), 01006 Vitoria-Gasteiz, Spain
| | - María Aranzazu Goicolea
- Department of Analytical Chemistry, Faculty of Pharmacy, University of the Basque Country (UPV/EHU), 01006 Vitoria-Gasteiz, Spain
| | - Joan Sallés
- Bioaraba, Neurofarmacología Celular y Molecular, 01008 Vitoria-Gasteiz, Spain
- Department of Pharmacology, Faculty of Pharmacy, University of the Basque Country (UPV/EHU), 01006 Vitoria-Gasteiz, Spain
- Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), 28029 Madrid, Spain
- Correspondence: ; Tel.: +34-945-013114
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20
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Pan HT, Xi ZQ, Wei XQ, Wang K. A network pharmacology approach to predict potential targets and mechanisms of " Ramulus Cinnamomi (cassiae) - Paeonia lactiflora" herb pair in the treatment of chronic pain with comorbid anxiety and depression. Ann Med 2022; 54:413-425. [PMID: 35098831 PMCID: PMC8812742 DOI: 10.1080/07853890.2022.2031268] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Traditional Chinese medicine (TCM) prescriptions have multiple bioactive properties. "Gui Zhi-Shao Yao" herb pair is widely used to treat chronic pain (CP), as well as anxiety and depression. However, its related targets and underlying mechanisms have not been deciphered. METHODS In this study, the network pharmacology method was used to explore the bioactive components and targets of "Gui Zhi-Shao Yao" herb pair and further elucidate its potential biological mechanisms of action in the treatment of CP with comorbid anxiety disorder (AD) and mental depression (MD). RESULTS Following a series of analyses, we identified 15 active compounds, hitting 130 potential targets. After the intersections the targets of this herb pair and CP, AD and MD - sorted by the value of degree - nine targets were identified as the vital ones: Akt1, IL6, TNF, PTGS2, JUN, CASP3, MAPK8, PPARγ and NOS3. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis results demonstrated 11 pathways, such as AGE-RAGE signalling pathway, IL-17 signalling pathway, TNF signalling pathway, which primarily participate in the pathological processes. CONCLUSIONS This study preliminarily predicted and verified the pharmacological and molecular mechanisms of "Gui Zhi-Shao Yao" herb pair for treating CP with comorbid AD and MD from a holistic perspective. In vivo and in vitro experiments will be required to further investigate the mechanisms.KEY MESSAGEA network pharmacology approach was applied to identify key targets and molecular mechanisms.Nine targets were regarded as the vital targets for chronic pain with comorbid anxiety and depression.Predicted 11 pathways were the potential therapy targets and pharmacological mechanism of "Gui Zhi-Shao Yao" herb pair.
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Affiliation(s)
- Hao-Tian Pan
- Acupuncture Anesthesia Clinical Research Institute, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Zi-Qi Xi
- Acupuncture Anesthesia Clinical Research Institute, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Xu-Qiang Wei
- Acupuncture Anesthesia Clinical Research Institute, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Ke Wang
- Acupuncture Anesthesia Clinical Research Institute, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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21
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Roberts CJ, Hopp FA, Hogan QH, Dean C. Anandamide in the dorsal periaqueductal gray inhibits sensory input without a correlation to sympathoexcitation. NEUROBIOLOGY OF PAIN (CAMBRIDGE, MASS.) 2022; 12:100104. [PMID: 36531614 PMCID: PMC9755024 DOI: 10.1016/j.ynpai.2022.100104] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Revised: 09/09/2022] [Accepted: 09/15/2022] [Indexed: 01/11/2023]
Abstract
There is growing literature supporting cannabinoids as a potential therapeutic for pain conditions. The development of chronic pain has been associated with reduced concentrations of the endogenous cannabinoid anandamide (AEA) in the midbrain dorsal periaqueductal gray (dPAG), and microinjections of synthetic cannabinoids into the dPAG are antinociceptive. Therefore, the goal of this study was to examine the role of the dPAG in cannabinoid-mediated sensory inhibition. Given that cannabinoids in the dPAG also elicit sympathoexcitation, a secondary goal was to assess coordination between sympathetic and antinociceptive responses. AEA was microinjected into the dPAG while recording single unit activity of wide dynamic range (WDR) dorsal horn neurons (DHNs) evoked by high intensity mechanical stimulation of the hindpaw, concurrently with renal sympathetic nerve activity (RSNA), in anesthetized male rats. AEA microinjected into the dPAG decreased evoked DHN activity (n = 24 units), for half of which AEA also elicited sympathoexcitation. AEA actions were mediated by cannabinoid 1 receptors as confirmed by local pretreatment with the cannabinoid receptor antagonist AM281. dPAG microinjection of the synaptic excitant DL-homocysteic acid (DLH) also decreased evoked DHN activity (n = 27 units), but in all cases this was accompanied by sympathoexcitation. Thus, sensory inhibition elicited from the dPAG is not exclusively linked with sympathoexcitation, suggesting discrete neuronal circuits. The rostrocaudal location of sites may affect evoked responses as AEA produced sensory inhibition without sympathetic effects at 86 % of caudal compared to 25 % of rostral sites, supporting anatomically distinct neurocircuits. These data indicate that spatially selective manipulation of cannabinoid signaling could provide analgesia without potentially harmful autonomic activation.
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Key Words
- AEA, N-arachidonylethanolamine, anandamide
- Antinociception
- CB1R, cannabinoid type one receptor
- CV, cardiovascular
- Cannabinoid
- DHN, dorsal horn neuron
- DLH, DL-homocysteic acid
- Dorsal horn
- FAAH, fatty acid amide hydrolase
- GPCR, G protein-coupled receptor
- IML, intermediolateral cell column
- MAP, mean arterial pressure
- NTS, nucleus tractus solitarius
- PAG, periaqueductal gray
- PPAR, peroxisome proliferator activated receptor
- RSNA, renal sympathetic nerve activity
- RVLM, rostral ventrolateral medulla
- RVMM, rostral ventromedial medulla
- Rat
- SIA, stress-induced analgesia
- SNS, sympathetic nervous system
- Sympathetic nervous system
- TRPV1, transient receptor potential vanilloid type 1
- WDR, wide dynamic range
- dPAG, dorsal periaqueductal gray
- vPAG, ventral periaqueductal gray
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Affiliation(s)
- Christopher J. Roberts
- Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, WI 53226, USA,Department of Anesthesiology, Zablocki Veterans Affairs Medical Center, Milwaukee, WI 53295, USA
| | - Francis A. Hopp
- Department of Anesthesiology, Zablocki Veterans Affairs Medical Center, Milwaukee, WI 53295, USA
| | - Quinn H. Hogan
- Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, WI 53226, USA,Department of Anesthesiology, Zablocki Veterans Affairs Medical Center, Milwaukee, WI 53295, USA
| | - Caron Dean
- Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, WI 53226, USA,Department of Anesthesiology, Zablocki Veterans Affairs Medical Center, Milwaukee, WI 53295, USA,Corresponding author at: Department of Anesthesiology, Research Service 151, Zablocki VA Medical Center, Milwaukee, WI 53295, USA.
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22
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Maixner D, Christy D, Kong L, Viatchenko-Karpinski V, Horner A, Hooks S, Weng HR. Phytohormone abscisic acid ameliorates neuropathic pain via regulating LANCL2 protein abundance and glial activation at the spinal cord. Mol Pain 2022; 18:17448069221107781. [PMID: 35647699 PMCID: PMC9248043 DOI: 10.1177/17448069221107781] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Spinal neuroinflammation plays a critical role in the genesis of neuropathic
pain. Accumulating data suggest that abscisic acid (ABA), a phytohormone,
regulates inflammatory processes in mammals. In this study, we found that
reduction of the LANCL2 receptor protein but not the agonist ABA in the spinal
cord is associated with the genesis of neuropathic pain. Systemic or intrathecal
administration of ABA ameliorates the development and pre-existence of
mechanical allodynia and heat hyperalgesia in animals with partial sciatic nerve
ligation (pSNL). LANCL2 is expressed only in microglia in the spinal dorsal
horn. Pre-emptive treatment with ABA attenuates activation of microglia and
astrocytes, ERK activity, and TNFα protein abundance in the dorsal horn in rats
with pSNL. These are accompanied by restoration of spinal LANCL2 protein
abundance. Spinal knockdown of LANCL2 gene with siRNA recapitulates the
behavioral and spinal molecular changes induced by pSNL. Activation of spinal
toll-like receptor 4 (TLR4) with lipopolysaccharide leads to activation of
microglia, and over production of TNFα, which are concurrently accompanied by
suppression of protein levels of LANCL2 and peroxisome proliferator
activated-receptor γ. These changes are ameliorated when ABA is added with LPS.
The anti-inflammatory effects induced by ABA do not requires Gi
protein activity. Our study reveals that the ABA/LANCL2 system is a powerful
endogenous system regulating spinal neuroinflammation and nociceptive
processing, suggesting the potential utility of ABA as the management of
neuropathic pain.
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Affiliation(s)
- Dylan Maixner
- Pharmaceutical and Biomedical Sciences15506University of Georgia College of Pharmacy
| | | | | | | | | | | | - Han-Rong Weng
- Basic Sciences436933California Northstate University
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Trindade da Silva CA, Clemente-Napimoga JT, Abdalla HB, Basting RT, Napimoga MH. Peroxisome proliferator-activated receptor-gamma (PPARγ) and its immunomodulation function: current understanding and future therapeutic implications. Expert Rev Clin Pharmacol 2022; 15:295-303. [PMID: 35481412 DOI: 10.1080/17512433.2022.2071697] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
INTRODUCTION : Pain is a multidimensional experience involving the biological, psychological, and social dimensions of each individual. Particularly, the biological aspects of pain conditions are a response of the neuroimmunology system and the control of painful conditions is a worldwide challenge for researchers. Although years of investigation on pain experience and treatment exist, the high prevalence of chronic pain is still a fact. AREAS COVERED : Peroxisome proliferator-activated receptor-gamma (PPARγ) is a ligand-activated transcription factor belonging to the nuclear hormone receptor superfamily. It regulates several metabolic pathways, including lipid biosynthesis and glucose metabolism, when activated. However, PPARγ activation also has a critical immunomodulatory and neuroprotective effect. EXPERT OPINION : This review summarizes the evidence of synthetic or natural PPARγ ligands such as 15d-PGJ2, epoxyeicosatrienoic acids, thiazolidinediones, and specialized pro-resolving mediators, representing an interesting therapeutic tool for pain control.
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Affiliation(s)
- Carlos Antonio Trindade da Silva
- Laboratoy of Neuroimmune Interface of Pain Research, Faculdade São Leopoldo Mandic, Instituto de Pesquisas São Leopoldo Mandic Campinas, SP, Brazil
| | - Juliana Trindade Clemente-Napimoga
- Laboratoy of Neuroimmune Interface of Pain Research, Faculdade São Leopoldo Mandic, Instituto de Pesquisas São Leopoldo Mandic Campinas, SP, Brazil
| | - Henrique Ballassini Abdalla
- Laboratoy of Neuroimmune Interface of Pain Research, Faculdade São Leopoldo Mandic, Instituto de Pesquisas São Leopoldo Mandic Campinas, SP, Brazil
| | - Rosanna Tarkany Basting
- Laboratoy of Neuroimmune Interface of Pain Research, Faculdade São Leopoldo Mandic, Instituto de Pesquisas São Leopoldo Mandic Campinas, SP, Brazil
| | - Marcelo Henrique Napimoga
- Laboratoy of Neuroimmune Interface of Pain Research, Faculdade São Leopoldo Mandic, Instituto de Pesquisas São Leopoldo Mandic Campinas, SP, Brazil
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Effects of Intra-BLA Administration of PPAR Antagonists on Formalin-Evoked Nociceptive Behaviour, Fear-Conditioned Analgesia, and Conditioned Fear in the Presence or Absence of Nociceptive Tone in Rats. MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27062021. [PMID: 35335382 PMCID: PMC8949000 DOI: 10.3390/molecules27062021] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Revised: 03/02/2022] [Accepted: 03/03/2022] [Indexed: 11/16/2022]
Abstract
There is evidence for the involvement of peroxisome proliferator-activated receptors (PPARs) in pain, cognition, and anxiety. However, their role in pain–fear interactions is unknown. The amygdala plays a key role in pain, conditioned fear, and fear-conditioned analgesia (FCA). We investigated the effects of intra-basolateral amygdala (BLA) administration of PPARα, PPARβ/δ, and PPARγ antagonists on nociceptive behaviour, FCA, and conditioned fear in the presence or absence of nociceptive tone. Male Sprague-Dawley (SD) rats received footshock (FC) or no footshock (NFC) in a conditioning arena. Twenty-three and a half hours later, rats received an intraplantar injection of formalin or saline and, 15 min later, intra-BLA microinjections of vehicle, PPARα (GW6471) PPARβ/δ (GSK0660), or PPARγ (GW9662) antagonists before arena re-exposure. Pain and fear-related behaviour were assessed, and neurotransmitters/endocannabinoids measured post-mortem. Intra-BLA administration of PPARα or PPARγ antagonists potentiated freezing in the presence of nociceptive tone. Blockade of all PPAR subtypes in the BLA increased freezing and BLA dopamine levels in NFC rats in the absence of nociceptive tone. Administration of intra-BLA PPARα and PPARγ antagonists increased levels of dopamine in the BLA compared with the vehicle-treated counterparts. In conclusion, PPARα and PPARγ in the BLA play a role in the expression or extinction of conditioned fear in the presence or absence of nociceptive tone.
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25
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Yang P, Li Z, Du W, Wu C, Xiong W. Hepatoprotective role of peroxisome proliferator-activated receptor-α in non-cancerous hepatic tissues following transcatheter arterial embolization. Open Life Sci 2022; 17:827-838. [PMID: 36045714 PMCID: PMC9372709 DOI: 10.1515/biol-2022-0068] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Revised: 02/10/2022] [Accepted: 03/12/2022] [Indexed: 12/24/2022] Open
Abstract
Transcatheter arterial embolization (TAE) is a widely used technique in treating hepatic carcinoma but may cause liver injury in some cases. This study investigated the hepatoprotective effect of the preprocessed peroxisome proliferator-activated receptor-α (PPAR-α) agonist-WY-14643 following TAE. A total of 60 rabbit liver cancer models were developed and divided into a combined treatment (WY-14643 and TAE), TAE, and control groups. After TAE, we examined the histopathological picture and liver functions. Further, the expression of antioxidant enzymes, tumor necrosis factor-α (TNF-α), nuclear factor of κ-light chain of enhancer-activated B cells (NF-κB), PPAR-α, and B-cell lymphoma-2 (Bcl-2) was analyzed. Liver function tests, pathology score, and apoptosis index significantly worsened in the TAE group but were normalized in the combined treatment group. In addition, ELISA results showed that antioxidant enzyme activity significantly increased, while the malondialdehyde content and level of inflammatory cytokines were significantly reduced in the combined treatment group. Furthermore, compared to the TAE group, the expressions of PPAR-α, antioxidant enzymes superoxide dismutase1 (SOD1) and SOD2, and Bcl-2 were significantly elevated, while NF-κB was significantly reduced in the combined treatment group. On the other hand, the expression of NF-κB in tumor tissues was significantly reduced by pretreatment with WY-14643. Therefore, PPAR-α can ameliorate liver injury by exerting its anti-oxidative, anti-inflammatory, and anti-apoptotic functions.
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Affiliation(s)
- Peiyu Yang
- School of Clinical Medicine, Dali University, Dali City, Yunnan Province 671000, China
| | - Zhengliang Li
- Department of Radiology, The First Affiliated Hospital of Dali University, No. 32, Jiashibo Street, Dali City, Yunnan Province 671000, People’s Republic of China
| | - Wei Du
- Department of Radiology, The First Affiliated Hospital of Dali University, No. 32, Jiashibo Street, Dali City, Yunnan Province 671000, People’s Republic of China
| | - Chunhua Wu
- Department of Radiology, The First Affiliated Hospital of Dali University, No. 32, Jiashibo Street, Dali City, Yunnan Province 671000, People’s Republic of China
| | - Wencui Xiong
- School of Clinical Medicine, Dali University, Dali City, Yunnan Province 671000, China
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26
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Silva NR, Gomes FIF, Lopes AHP, Cortez IL, Dos Santos JC, Silva CEA, Mechoulam R, Gomes FV, Cunha TM, Guimarães FS. The Cannabidiol Analog PECS-101 Prevents Chemotherapy-Induced Neuropathic Pain via PPARγ Receptors. Neurotherapeutics 2022; 19:434-449. [PMID: 34904193 PMCID: PMC9130439 DOI: 10.1007/s13311-021-01164-w] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/12/2021] [Indexed: 01/03/2023] Open
Abstract
Chemotherapy-induced peripheral neuropathy (CIPN) is the main dose-limiting adverse effect of chemotherapy drugs such as paclitaxel (PTX). PTX causes marked molecular and cellular damage, mainly in the peripheral nervous system, including sensory neurons in the dorsal root ganglia (DRG). Several studies have shown the therapeutic potential of cannabinoids, including cannabidiol (CBD), the major non-psychotomimetic compound found in the Cannabis plant, to treat peripheral neuropathies. Here, we investigated the efficacy of PECS-101 (former HUF-101), a CBD fluorinated analog, on PTX-induced neuropathic pain in mice. PECS-101, administered after the end of treatment with PTX, did not reverse mechanical allodynia. However, PECS-101 (1 mg/kg) administered along with PTX treatment caused a long-lasting relief of the mechanical and cold allodynia. These effects were blocked by a PPARγ, but not CB1 and CB2 receptor antagonists. Notably, the effects of PECS-101 on the relief of PTX-induced mechanical and cold allodynia were not found in macrophage-specific PPARγ-deficient mice. PECS-101 also decreased PTX-induced increase in Tnf, Il6, and Aif1 (Iba-1) gene expression in the DRGs and the loss of intra-epidermal nerve fibers. PECS-101 did not alter motor coordination, produce tolerance, or show abuse potential. In addition, PECS-101 did not interfere with the chemotherapeutic effects of PTX. Thus, PECS-101, a new fluorinated CBD analog, could represent a novel therapeutic alternative to prevent mechanical and cold allodynia induced by PTX potentially through the activation of PPARγ in macrophages.
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Affiliation(s)
- Nicole Rodrigues Silva
- Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil.
| | | | | | - Isadora Lopes Cortez
- Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil
| | | | - Conceição Elidianne Aníbal Silva
- Center for Research in Inflammatory Diseases (CRID), Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil
| | - Raphael Mechoulam
- Department of Medicinal Chemistry and Natural Products, Hebrew University Medical Faculty, Jerusalem, Israel
| | - Felipe Villela Gomes
- Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil
| | - Thiago Mattar Cunha
- Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil.
- Center for Research in Inflammatory Diseases (CRID), Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil.
| | - Francisco Silveira Guimarães
- Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil.
- National Institute of Science and Translational Medicine, Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil.
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Advances in the role of natural products in human gene expression. Chin J Nat Med 2022; 20:1-8. [DOI: 10.1016/s1875-5364(22)60147-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Indexed: 11/17/2022]
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Anand U, Oldfield C, Pacchetti B, Anand P, Sodergren MH. Dose-Related Inhibition of Capsaicin Responses by Cannabinoids CBG, CBD, THC and their Combination in Cultured Sensory Neurons. J Pain Res 2021; 14:3603-3614. [PMID: 34853533 PMCID: PMC8627890 DOI: 10.2147/jpr.s336773] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Accepted: 11/05/2021] [Indexed: 01/18/2023] Open
Abstract
BACKGROUND The analgesic effects of Cannabis sativa are mediated by ∆9 tetrahydrocannabinol (THC), but the contributions of other bioactive complex components, including cannabigerol (CBG) and cannabidiol (CBD), are unclear. We describe the individual and combined effects of CBG, CBD and THC, on blocking capsaicin responses in dorsal root ganglion (DRG) neurons, in an in vitro model of nociceptor hypersensitivity. MATERIALS AND METHODS Adult rat DRG were dissected and enzyme digested to obtain a neuronal suspension in BSF2 medium containing 2% fetal calf serum, and the neurotrophic factors NGF and GDNF. After 48 h, cultured neurons were loaded with Fura-2 AM, to determine the effects of cannabinoids on capsaicin responses using calcium imaging. In control experiments, neurons were treated with vehicle, followed by 1 µM capsaicin. In cannabinoid treated cultures, CBG, CBD or THC were applied individually, or combined (1:1:1 ratio), followed by 1 µM capsaicin. Data from n = 6 experiments were analysed with Student's t-test and Pearson's correlation coefficient. RESULTS CBG, CBD and THC, applied individually, elicited dose-related calcium influx in a subset of DRG neurons, and a corresponding dose-related reduction of subsequent responses to capsaicin. Maximum inhibition of capsaicin responses was observed at 30 µM CBG, 100 µM CBD, and 100 µM THC individually, and with combined CBD+CBG+THC (1:1:1) at 90 µM. THC+CBD+CBG combined in a 1:1:1 proportion has the potential to enhance the potency of these compounds applied individually. There was a high correlation between cannabinoid-mediated calcium influx and reduction of capsaicin responses: CBG = -0.88, THC = -0.97, CBD = -0.99 and combined CBG + THC + CBD = -1.00. CONCLUSION CBG, CBD and THC demonstrated potent dose-related inhibition of capsaicin responses in DRG neurons when applied individually in vitro, and enhanced when applied in combination, being most effective at 90 μM. Thus, efficacy and tolerability of THC could be improved in combination with CBG and CBD at optimal concentrations, which deserve further studies in vivo.
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Affiliation(s)
- Uma Anand
- Faculty of Medicine, Imperial College London, Hammersmith Hospital, London, W12 ONN, UK
| | - Christian Oldfield
- Faculty of Medicine, Imperial College London, Hammersmith Hospital, London, W12 ONN, UK
| | | | - Praveen Anand
- Faculty of Medicine, Imperial College London, Hammersmith Hospital, London, W12 ONN, UK
| | - Mikael H Sodergren
- Faculty of Medicine, Imperial College London, Hammersmith Hospital, London, W12 ONN, UK
- EMMAC Life Sciences Ltd, London, UK
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Sexually Dimorphic Expression of Fear-conditioned Analgesia in Rats and Associated Alterations in the Endocannabinoid System in the Periaqueductal Grey. Neuroscience 2021; 480:117-130. [PMID: 34774710 DOI: 10.1016/j.neuroscience.2021.11.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Revised: 10/16/2021] [Accepted: 11/02/2021] [Indexed: 11/20/2022]
Abstract
The endocannabinoid system within the periaqueductal grey (PAG) has been implicated in fear-conditioned analgesia (FCA), the profound suppression of pain upon re-exposure to a context previously paired with an aversive stimulus. Since the endocannabinoid and nociceptive systems exhibit sexual dimorphism, the aim of the present study was to assess possible sex differences in the expression of FCA, fear in the presence of nociceptive tone, and associated sex-dependent alterations in the endocannabinoid system within the PAG. Male and female Sprague-Dawley rats received footshock (10 × 1s; 0.4 mA; every 60 s) or no-footshock in a conditioning arena and 23.5 h later received intraplantar injection of formalin (2.5%) under brief isoflourane anaesthetic into the right hind paw. Nociceptive and fear-related behaviours were assessed 30 min later. Levels of endocannabinoids, N-acylethanolamines and neurotransmitters in the PAG were assessed by LC-MS/MS and expression of endocannabinoid system-related proteins by Western immunoblotting. Male, but not female, rats exhibited robust FCA and greater expression of fear-related behaviours than females. Fear-conditioned formalin-treated males, but not females, had higher levels of N-oleoylethanolamine (OEA) and γ-aminobutyric acid (GABA) in the PAG, compared with non-fear-conditioned controls. There was no effect of fear conditioning on the levels of FAAH or CB1 receptor expression (CB1R) in the PAG of male or female formalin-treated rats. Non-fear-conditioned females had higher levels of CB1R and PPARγ expression than non-fear-conditioned male counterparts. In summary, our results provide evidence of sexual dimorphism in the expression of FCA and fear-related behaviours, and associated alterations in components of the endocannabinoid system and GABA within the PAG.
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Interplay between Prokineticins and Histone Demethylase KDM6A in a Murine Model of Bortezomib-Induced Neuropathy. Int J Mol Sci 2021; 22:ijms222111913. [PMID: 34769347 PMCID: PMC8584499 DOI: 10.3390/ijms222111913] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Revised: 10/27/2021] [Accepted: 10/29/2021] [Indexed: 11/17/2022] Open
Abstract
Chemotherapy-induced neuropathy (CIN) is a major adverse effect associated with many chemotherapeutics, including bortezomib (BTZ). Several mechanisms are involved in CIN, and recently a role has been proposed for prokineticins (PKs), a chemokine family that induces proinflammatory/pro-algogen mediator release and drives the epigenetic control of genes involved in cellular differentiation. The present study evaluated the relationships between epigenetic mechanisms and PKs in a mice model of BTZ-induced painful neuropathy. To this end, spinal cord alterations of histone demethylase KDM6A, nuclear receptors PPARα/PPARγ, PK2, and pro-inflammatory cytokines IL-6 and IL-1β were assessed in neuropathic mice treated with the PK receptors (PKRs) antagonist PC1. BTZ treatment promoted a precocious upregulation of KDM6A, PPARs, and IL-6, and a delayed increase of PK2 and IL-1β. PC1 counteracted allodynia and prevented the increase of PK2 and of IL-1β in BTZ neuropathic mice. The blockade of PKRs signaling also opposed to KDM6A increase and induced an upregulation of PPAR gene transcription. These data showed the involvement of epigenetic modulatory enzymes in spinal tissue phenomena associated with BTZ painful neuropathy and underline a role of PKs in sustaining the increase of proinflammatory cytokines and in exerting an inhibitory control on the expression of PPARs through the regulation of KDM6A gene expression in the spinal cord.
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Pharmacological Blockade of PPARα Exacerbates Inflammatory Pain-Related Impairment of Spatial Memory in Rats. Biomedicines 2021; 9:biomedicines9060610. [PMID: 34072060 PMCID: PMC8227714 DOI: 10.3390/biomedicines9060610] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 05/25/2021] [Accepted: 05/26/2021] [Indexed: 12/17/2022] Open
Abstract
Peroxisome proliferator-activated receptors (PPARs) are ligand-dependent transcription factors that exist in three isoforms: PPARα, PPARβ/δ and PPARγ. Studies suggest that the PPAR signalling system may modulate pain, anxiety and cognition. The aim of the present study was to investigate whether endogenous signalling via PPARs differentially modulates innate anxiety responses and mnemonic function in the presence and absence of inflammatory pain. We examined the effects of intraperitoneal administration of GW6471 (PPARα antagonist), GSK0660 (PPARβ/δ antagonist), GW9662 (PPARγ antagonist), and N-palmitoylethanolamide (PEA) on rat behaviour in the elevated plus maze (EPM), open field (OF), light-dark box (LDB), and novel object recognition (NOR) tests in the presence or absence of chronic inflammatory pain. Complete Freund’s Adjuvant (CFA)-injected rats exhibited impaired recognition and spatial mnemonic performance in the NOR test and pharmacological blockade of PPARα further impaired spatial memory in CFA-treated rats. N-oleoylethanolamide (OEA) levels were higher in the dorsal hippocampus in CFA-injected animals compared to their counterparts. The results suggest a modulatory effect of CFA-induced chronic inflammatory pain on cognitive processing, but not on innate anxiety-related responses. Increased OEA-PPARα signalling may act as a compensatory mechanism to preserve spatial memory function following CFA injection.
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Khasabova IA, Seybold VS, Simone DA. The role of PPARγ in chemotherapy-evoked pain. Neurosci Lett 2021; 753:135845. [PMID: 33774149 PMCID: PMC8089062 DOI: 10.1016/j.neulet.2021.135845] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2020] [Revised: 02/27/2021] [Accepted: 03/19/2021] [Indexed: 12/13/2022]
Abstract
Although millions of people are diagnosed with cancer each year, survival has never been greater thanks to early diagnosis and treatments. Powerful chemotherapeutic agents are highly toxic to cancer cells, but because they typically do not target cancer cells selectively, they are often toxic to other cells and produce a variety of side effects. In particular, many common chemotherapies damage the peripheral nervous system and produce neuropathy that includes a progressive degeneration of peripheral nerve fibers. Chemotherapy-induced peripheral neuropathy (CIPN) can affect all nerve fibers, but sensory neuropathies are the most common, initially affecting the distal extremities. Symptoms include impaired tactile sensitivity, tingling, numbness, paraesthesia, dysesthesia, and pain. Since neuropathic pain is difficult to manage, and because degenerated nerve fibers may not grow back and regain normal function, considerable research has focused on understanding how chemotherapy causes painful CIPN so it can be prevented. Due to the fact that both therapeutic and side effects of chemotherapy are primarily associated with the accumulation of reactive oxygen species (ROS) and oxidative stress, this review focuses on the activation of endogenous antioxidant pathways, especially PPARγ, in order to prevent the development of CIPN and associated pain. The use of synthetic and natural PPARγ agonists to prevent CIPN is discussed.
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Affiliation(s)
- Iryna A Khasabova
- Department of Diagnostic and Biological Sciences, University of Minnesota, School of Dentistry, Minneapolis, MN, 55455, United States
| | - Virginia S Seybold
- Department of Diagnostic and Biological Sciences, University of Minnesota, School of Dentistry, Minneapolis, MN, 55455, United States
| | - Donald A Simone
- Department of Diagnostic and Biological Sciences, University of Minnesota, School of Dentistry, Minneapolis, MN, 55455, United States.
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Therapeutic Potential of Polyphenols in the Management of Diabetic Neuropathy. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2021; 2021:9940169. [PMID: 34093722 PMCID: PMC8137294 DOI: 10.1155/2021/9940169] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Accepted: 04/27/2021] [Indexed: 12/12/2022]
Abstract
Diabetic neuropathy (DN) is a common and serious diabetes-associated complication that primarily takes place because of neuronal dysfunction in patients with diabetes. Use of current therapeutic agents in DN treatment is quite challenging because of their severe adverse effects. Therefore, there is an increased need of identifying new safe and effective therapeutic agents. DN complications are associated with poor glycemic control and metabolic imbalances, primarily oxidative stress (OS) and inflammation. Various mediators and signaling pathways such as glutamate pathway, activation of channels, trophic factors, inflammation, OS, advanced glycation end products, and polyol pathway have a significant contribution to the progression and pathogenesis of DN. It has been indicated that polyphenols have the potential to affect DN pathogenesis and could be used as potential alternative therapy. Several polyphenols including kolaviron, resveratrol, naringenin, quercetin, kaempferol, and curcumin have been administered in patients with DN. Furthermore, chlorogenic acid can provide protection against glutamate neurotoxicity via its hydrolysate, caffeoyl acid group, and caffeic acid through regulating the entry of calcium into neurons. Epigallocatechin-3-gallate treatment can protect motor neurons by regulating the glutamate level. It has been demonstrated that these polyphenols can be promising in combating DN-associated damaging pathways. In this article, we have summarized DN-associated metabolic pathways and clinical manifestations. Finally, we have also focused on the roles of polyphenols in the treatment of DN.
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Obeng S, Hiranita T, León F, McMahon LR, McCurdy CR. Novel Approaches, Drug Candidates, and Targets in Pain Drug Discovery. J Med Chem 2021; 64:6523-6548. [PMID: 33956427 DOI: 10.1021/acs.jmedchem.1c00028] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Because of the problems associated with opioids, drug discovery efforts have been employed to develop opioids with reduced side effects using approaches such as biased opioid agonism, multifunctional opioids, and allosteric modulation of opioid receptors. Receptor targets such as adrenergic, cannabinoid, P2X3 and P2X7, NMDA, serotonin, and sigma, as well as ion channels like the voltage-gated sodium channels Nav1.7 and Nav1.8 have been targeted to develop novel analgesics. Several enzymes, such as soluble epoxide hydrolase, sepiapterin reductase, and MAGL/FAAH, have also been targeted to develop novel analgesics. In this review, old and recent targets involved in pain signaling and compounds acting at these targets are summarized. In addition, strategies employed to reduce side effects, increase potency, and efficacy of opioids are also elaborated. This review should aid in propelling drug discovery efforts to discover novel analgesics.
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Affiliation(s)
- Samuel Obeng
- Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, Florida 32610, United States.,Department Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, Florida 32610, United States
| | - Takato Hiranita
- Department Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, Florida 32610, United States
| | - Francisco León
- Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia 29208, United States
| | - Lance R McMahon
- Department Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, Florida 32610, United States
| | - Christopher R McCurdy
- Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, Florida 32610, United States.,Translational Drug Development Core, Clinical and Translational Sciences Institute, University of Florida, Gainesville, Florida 32610, United States
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35
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Calapai F, Mondello E, Mannucci C, Sorbara EE, Gangemi S, Quattrone D, Calapai G, Cardia L. Pain Biomarkers in Cancer: An Overview. Curr Pharm Des 2021; 27:293-304. [PMID: 33138755 DOI: 10.2174/1381612826666201102103520] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2020] [Accepted: 08/09/2020] [Indexed: 11/22/2022]
Abstract
BACKGROUND Pain is a common symptom in oncologic patients and its management is generally guided with reference to pain individually perceived by patients and expressed through self-reported scales. However, the utility of these tools is limited as it strongly depends on patients' opinions. For this reason, more objective instruments are desirable. OBJECTIVE In this overview, scientific articles indicating potential markers to be used for pain management in cancer were collected and discussed. METHODS Research was performed on principal electronic scientific databases by using the words "pain", "cancer", "markers" and "biomarkers" as the main keywords, and findings describing potential biomarkers for the management of cancer pain were reported. RESULTS Studies on pain markers not specific for cancer typology (inflammatory, genetic markers predicting response to analgesic drugs, neuroimaging markers) and pain markers for specific types of cancer (bone cancer, breast cancer, lung cancer, head and neck cancer, prostate cancer, cancer in pediatrics) have been presented and commented on. CONCLUSION This overview supports the view of the involvement of inflammatory mediators in the mechanisms underlying cancer pain. Only a small amount of data from research up till today is available on markers that can help in the management of pain, except for pro-inflammatory cytokines and other inflammatory indexes such as C-reactive protein (CRP). However, biomarkers are a promising strategy useful to predict pain intensity and to objectively quantify analgesic response in guiding decisions regarding individual-tailored treatments for cancer patients.
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Affiliation(s)
- Fabrizio Calapai
- Department of Biomedical and Dental Sciences and Morphological and Functional Imaging - University of Messina, Messina, Italy
| | - Epifanio Mondello
- Anesthesia, Intensive Care and Pain Therapy, Policlinico "G. Martino" - University of Messina, Messina, Italy
| | - Carmen Mannucci
- Department of Biomedical and Dental Sciences and Morphological and Functional Imaging - University of Messina, Messina, Italy
| | - Emanuela E Sorbara
- Department of Biomedical and Dental Sciences and Morphological and Functional Imaging - University of Messina, Messina, Italy
| | - Sebastiano Gangemi
- School and Division of Allergy and Clinical Immunology, Department of Experimental Medicine, University of Messina, Messina, Italy
| | - Domenico Quattrone
- Pain Therapy Unit, Grande Ospedale Metropolitano "Bianchi-Melacrino-Morelli" - Reggio Calabria, Italy
| | - Gioacchino Calapai
- Department of Biomedical and Dental Sciences and Morphological and Functional Imaging - University of Messina, Messina, Italy
| | - Luigi Cardia
- IRCCS Centro Neurolesi Bonino- Pulejo, Messina, Italy
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36
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Anand U, Pacchetti B, Anand P, Sodergren MH. Cannabis-based medicines and pain: a review of potential synergistic and entourage effects. Pain Manag 2021; 11:395-403. [PMID: 33703917 DOI: 10.2217/pmt-2020-0110] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
The recent legalization of medicinal cannabis in several jurisdictions has spurred the development of therapeutic formulations for chronic pain. Unlike pure delta-9-tetrahydrocannabinol (THC), full-spectrum products contain naturally occurring cannabinoids and have been reported to show improved efficacy or tolerability, attributed to synergy between cannabinoids and other components in the cannabis plant. Although 'synergy' indicates that two or more active compounds may produce an additive or combined effect greater than their individual analgesic effect, potentiation of the biological effect of a compound by related but inactive compounds, in combination, was termed the 'entourage effect'. Here, we review current evidence for potential synergistic and entourage effects of cannabinoids in pain relief. However, definitive clinical trials and in vitro functional studies are still required.
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Affiliation(s)
- Uma Anand
- Faculty of Medicine, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 ONN, UK
| | | | - Praveen Anand
- Faculty of Medicine, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 ONN, UK
| | - Mikael Hans Sodergren
- Faculty of Medicine, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 ONN, UK
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Roudsari NM, Lashgari NA, Zandi N, Pazoki B, Momtaz S, Sahebkar A, Abdolghaffari AH. PPARγ: A turning point for irritable bowel syndrome treatment. Life Sci 2020; 257:118103. [PMID: 32681913 DOI: 10.1016/j.lfs.2020.118103] [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] [Received: 05/20/2020] [Revised: 07/05/2020] [Accepted: 07/12/2020] [Indexed: 02/06/2023]
Abstract
Irritable bowel syndrome (IBS) is a chronic functional gastrointestinal (GI) disorder with negative impacts on quality of life of patients. Although the etiology of the disease is still unclear, there are a set of mechanisms and factors involved in IBS pathogenesis. Visceral hypersensitivity, impaired gut barrier, along with minor inflammation and oxidative stress are the most important triggers for IBS induction. Activation of peroxisome proliferator activated receptor-γ (PPAR-γ) has been shown to improve gut barrier, downregulate pro-inflammatory cytokines, reduce free radical production through antioxidative mechanisms, and exert anti-nociceptive effects against somatic pain. An electronic search in PubMed, Google Scholar, Scopus, and Cochrane library was performed and relevant clinical, in vivo and in vitro articles published between 2004 and June 2020 were collected. Search terms included "Irritable Bowel Syndrome" OR "IBS" OR "visceral hypersensitivity" OR "motility dysfunction" AND "peroxisome proliferator activated receptors" OR "PPAR". Herein, the efficacy of PPARγ signaling as a potential target for IBS treatment is reviewed.
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Affiliation(s)
- Nazanin Momeni Roudsari
- Department of Toxicology & Pharmacology, Faculty of Pharmacy, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Naser-Aldin Lashgari
- Department of Toxicology & Pharmacology, Faculty of Pharmacy, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Nadia Zandi
- Tehran University of Medical Sciences, Tehran, Iran
| | | | - Saeideh Momtaz
- Medicinal Plants Research Center, Institute of Medicinal Plants, ACECR, Tehran, Iran; Toxicology and Diseases Group (TDG), Pharmaceutical Sciences Research Center (PSRC), The Institute of Pharmaceutical Sciences (TIPS), Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran; GI Pharmacology Interest Group (GPIG), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Amirhossein Sahebkar
- Halal Research Center of IRI, FDA, Tehran, Iran; Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; Polish Mother's Memorial Hospital Research Institute (PMMHRI), Lodz, Poland.
| | - Amir Hossein Abdolghaffari
- Department of Toxicology & Pharmacology, Faculty of Pharmacy, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Medicinal Plants Research Center, Institute of Medicinal Plants, ACECR, Tehran, Iran; Toxicology and Diseases Group (TDG), Pharmaceutical Sciences Research Center (PSRC), The Institute of Pharmaceutical Sciences (TIPS), Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran; GI Pharmacology Interest Group (GPIG), Universal Scientific Education and Research Network (USERN), Tehran, Iran.
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Zhou YQ, Liu DQ, Chen SP, Chen N, Sun J, Wang XM, Li DY, Tian YK, Ye DW. PPARγ activation mitigates mechanical allodynia in paclitaxel-induced neuropathic pain via induction of Nrf2/HO-1 signaling pathway. Biomed Pharmacother 2020; 129:110356. [PMID: 32535388 DOI: 10.1016/j.biopha.2020.110356] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2020] [Revised: 05/26/2020] [Accepted: 06/01/2020] [Indexed: 12/14/2022] Open
Abstract
Paclitaxel-induced neuropathic pain (PINP) is a dose-limiting side effect and is refractory to widely used analgesic drugs. Previous studies have demonstrated a protective role of peroxisome proliferator-activated receptor gama (PPARγ) in neuropathic pain. However, whether PPARγ activation could alleviate PINP remains to be elucidated. Our previous study has validated the analgesic effect of oltipraz, an nuclear factor erythroid-2 related factor 2 (Nrf2) activator, in a rat model of PINP. In this study, we tested the hypothesis that rosiglitazone, a selective agonist of PPARγ, could attenuate PINP through induction of Nrf2/heme oxygenase-1 (HO-1) signaling pathway. Paclitaxel was injected intraperitoneally on four alternate days to induce neuropathic pain. Paw withdrawal threshold was used to evaluate mechanical allodynia. Western blot and immunofluorescence were used to examine the expression and distribution of PPARγ, Nrf2 and HO-1 in the spinal cord. Our results showed that rosiglitazone attenuated established PINP and delayed the onset of PINP via activation of PPARγ, which were reversed by PPARγ antagonist GW9662. Moreover, rosiglitazone inhibited downregulation of PPARγ in the spinal cord of PINP rats. Furthermore, the analgesic effect of rosiglitazone against PINP was abolished by trigonelline, an Nrf2 inhibitor. Finally, rosiglitazone significantly increased expression of Nrf2 and HO-1 in the spinal cord of PINP rats. Collectively, these results indicated that PPARγ activation might mitigate PINP through activating spinal Nrf2/HO-1 signaling pathway. Our results may provide an alternative option for PINP patients.
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Affiliation(s)
- Ya-Qun Zhou
- Department of Anesthesiology and Pain Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Dai-Qiang Liu
- Department of Anesthesiology and Pain Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shu-Ping Chen
- Department of Anesthesiology and Pain Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Nan Chen
- Department of Anesthesiology and Pain Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jia Sun
- Department of Anesthesiology and Pain Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiao-Mei Wang
- Department of Anesthesiology and Pain Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Dan-Yang Li
- Department of Anesthesiology and Pain Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yu-Ke Tian
- Department of Anesthesiology and Pain Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
| | - Da-Wei Ye
- Cancer Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
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Shi Y, Zou Y, Shen Z, Xiong Y, Zhang W, Liu C, Chen S. Trace Elements, PPARs, and Metabolic Syndrome. Int J Mol Sci 2020; 21:E2612. [PMID: 32283758 PMCID: PMC7177711 DOI: 10.3390/ijms21072612] [Citation(s) in RCA: 65] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2020] [Revised: 04/06/2020] [Accepted: 04/07/2020] [Indexed: 12/13/2022] Open
Abstract
Metabolic syndrome (MetS) is a constellation of metabolic derangements, including central obesity, insulin resistance, hypertension, glucose intolerance, and dyslipidemia. The pathogenesis of MetS has been intensively studied, and now many factors are recognized to contribute to the development of MetS. Among these, trace elements influence the structure of proteins, enzymes, and complex carbohydrates, and thus an imbalance in trace elements is an independent risk factor for MetS. The molecular link between trace elements and metabolic homeostasis has been established, and peroxisome proliferator-activated receptors (PPARs) have appeared as key regulators bridging these two elements. This is because on one hand, PPARs are actively involved in various metabolic processes, such as abdominal adiposity and insulin sensitivity, and on the other hand, PPARs sensitively respond to changes in trace elements. For example, an iron overload attenuates hepatic mRNA expression of Ppar-α; zinc supplementation is considered to recover the DNA-binding activity of PPAR-α, which is impaired in steatotic mouse liver; selenium administration downregulates mRNA expression of Ppar-γ, thereby improving lipid metabolism and oxidative status in the liver of high-fat diet (HFD)-fed mice. More importantly, PPARs' expression and activity are under the control of the circadian clock and show a robust 24 h rhythmicity, which might be the reasons for the side effects and the clinical limitations of trace elements targeting PPARs. Taken together, understanding the casual relationships among trace elements, PPARs' actions, and the pathogenesis of MetS is of great importance. Further studies are required to explore the chronopharmacological effects of trace elements on the diurnal oscillation of PPARs and the consequent development of MetS.
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Affiliation(s)
| | | | | | | | | | | | - Siyu Chen
- State Key Laboratory of Natural Medicines and School of Life Science and Technology, China Pharmaceutical University, Nanjing 211198, China
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Westlund KN, Zhang M. Building and Testing PPARγ Therapeutic ELB00824 with an Improved Therapeutic Window for Neuropathic Pain. Molecules 2020; 25:E1120. [PMID: 32138198 PMCID: PMC7179195 DOI: 10.3390/molecules25051120] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2020] [Revised: 02/29/2020] [Accepted: 03/02/2020] [Indexed: 11/20/2022] Open
Abstract
Effective, non-addictive therapeutics for chronic pain remain a critical need. While there are several potential therapeutics that stimulate anti-inflammatory mechanisms to restore homeostasis in the spinal dorsal horn microenvironment, the effectiveness of drugs for neuropathic pain are still inadequate. The convergence of increasing knowledge about the multi-factorial mechanisms underlying neuropathic pain and the mechanisms of drug action from preclinical studies are providing the ability to create pharmaceuticals with better clinical effectiveness. By targeting and activating the peroxisome proliferator-activated receptor gamma subunit (PPARγ), numerous preclinical studies report pleiotropic effects of thiazolidinediones (TDZ) beyond their intended use of increasing insulin, including their anti-inflammatory, renal, cardioprotective, and oncopreventative effects. Several studies find TDZs reduce pain-related behavioral symptoms, including ongoing secondary hypersensitivity driven by central sensitization. Previous studies find increased PPARγ in the spinal cord and brain regions innervated by incoming afferent nerve endings after the induction of neuropathic pain models. PPARγ agonist treatment provides an effective reduction in pain-related behaviors, including anxiety. Data further suggest that improved brain mitochondrial bioenergetics after PPARγ agonist treatment is a key mechanism for reducing hypersensitivity. This review emphasizes two points relevant for the development of better chronic pain therapies. First, employing neuropathic pain models with chronic duration is critical since they can encompass the continuum of molecular and brain circuitry alterations arising over time when pain persists, providing greater relevance to clinical pain syndromes. Assisting in that effort are preclinical models of chronic trigeminal pain syndromes. Secondly, considering the access to nerve and brain neurons and glia across the blood-brain barrier is important. While many therapies have low brain penetrance, a PPARγ agonist with better brain penetrance, ELB00824, has been developed. Purposeful design and recent comparative testing indicate that ELB00824 is extraordinarily efficient and efficacious. ELB00824 provides greatly improved attenuation of pain-related behaviors, including mechanical hypersensitivity, anxiety, and depression in our chronic trigeminal nerve injury models. Physiochemical properties allowing significant brain access and toxicity testing are discussed.
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Affiliation(s)
- Karin N. Westlund
- Department of Anesthesiology & Critical Care Medicine, MSC10 6000, 2211 Lomas Blvd. NE, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA
| | - Morgan Zhang
- USA Elixiria Biotech Inc, 200 High Point Drive, Hartsdale, NY 10530, USA;
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Gaspar JC, Okine BN, Llorente-Berzal A, Roche M, Finn DP. Pharmacological Blockade of PPAR Isoforms Increases Conditioned Fear Responding in the Presence of Nociceptive Tone. Molecules 2020; 25:molecules25041007. [PMID: 32102354 PMCID: PMC7070536 DOI: 10.3390/molecules25041007] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2019] [Revised: 02/17/2020] [Accepted: 02/18/2020] [Indexed: 12/29/2022] Open
Abstract
Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors with three isoforms (PPARα, PPARβ/δ, PPARγ) and can regulate pain, anxiety, and cognition. However, their role in conditioned fear and pain-fear interactions has not yet been investigated. Here, we investigated the effects of systemically administered PPAR antagonists on formalin-evoked nociceptive behaviour, fear-conditioned analgesia (FCA), and conditioned fear in the presence of nociceptive tone in rats. Twenty-three and a half hours following fear conditioning to context, male Sprague-Dawley rats received an intraplantar injection of formalin and intraperitoneal administration of vehicle, PPARα (GW6471), PPARβ/δ (GSK0660) or PPARγ (GW9662) antagonists, and 30 min later were re-exposed to the conditioning arena for 15 min. The PPAR antagonists did not alter nociceptive behaviour or fear-conditioned analgesia. The PPARα and PPARβ/δ antagonists prolonged context-induced freezing in the presence of nociceptive tone without affecting its initial expression. The PPARγ antagonist potentiated freezing over the entire trial. In conclusion, pharmacological blockade of PPARα and PPARβ/δ in the presence of formalin-evoked nociceptive tone, impaired short-term, within-trial fear-extinction in rats without affecting pain response, while blockade of PPARγ potentiated conditioned fear responding. These results suggest that endogenous signalling through these three PPAR isoforms may reduce the expression of conditioned fear in the presence of nociceptive tone.
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Affiliation(s)
- Jessica C. Gaspar
- Pharmacology and Therapeutics Department, National University of Ireland Galway, University Road, H91 W5P7 Galway, Ireland; (J.C.G.); (B.N.O.); (A.L.-B.)
- Galway Neuroscience Centre, National University of Ireland Galway, University Road, H91 W5P7 Galway, Ireland;
- Centre for Pain Research, National University of Ireland Galway, University Road, H91 W5P7 Galway, Ireland
| | - Bright N. Okine
- Pharmacology and Therapeutics Department, National University of Ireland Galway, University Road, H91 W5P7 Galway, Ireland; (J.C.G.); (B.N.O.); (A.L.-B.)
- Galway Neuroscience Centre, National University of Ireland Galway, University Road, H91 W5P7 Galway, Ireland;
- Centre for Pain Research, National University of Ireland Galway, University Road, H91 W5P7 Galway, Ireland
| | - Alvaro Llorente-Berzal
- Pharmacology and Therapeutics Department, National University of Ireland Galway, University Road, H91 W5P7 Galway, Ireland; (J.C.G.); (B.N.O.); (A.L.-B.)
- Galway Neuroscience Centre, National University of Ireland Galway, University Road, H91 W5P7 Galway, Ireland;
- Centre for Pain Research, National University of Ireland Galway, University Road, H91 W5P7 Galway, Ireland
| | - Michelle Roche
- Galway Neuroscience Centre, National University of Ireland Galway, University Road, H91 W5P7 Galway, Ireland;
- Centre for Pain Research, National University of Ireland Galway, University Road, H91 W5P7 Galway, Ireland
- Physiology Department, National University of Ireland Galway, University Road, H91 W5P7 Galway, Ireland
| | - David P. Finn
- Pharmacology and Therapeutics Department, National University of Ireland Galway, University Road, H91 W5P7 Galway, Ireland; (J.C.G.); (B.N.O.); (A.L.-B.)
- Galway Neuroscience Centre, National University of Ireland Galway, University Road, H91 W5P7 Galway, Ireland;
- Physiology Department, National University of Ireland Galway, University Road, H91 W5P7 Galway, Ireland
- Correspondence: ; Tel.: +353-(0)91-495-280; Fax: +353-(0)91-495-586
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Lazic A, Popović J, Paunesku T, Woloschak GE, Stevanović M. Insights into platinum-induced peripheral neuropathy-current perspective. Neural Regen Res 2020; 15:1623-1630. [PMID: 32209761 PMCID: PMC7437596 DOI: 10.4103/1673-5374.276321] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Cancer is a global health problem that is often successfully addressed by therapy, with cancer survivors increasing in numbers and living longer world around. Although new cancer treatment options are continuously explored, platinum based chemotherapy agents remain in use due to their efficiency and availability. Unfortunately, all cancer therapies affect normal tissues as well as cancer, and more than 40 specific side effects of platinum based drugs documented so far decrease the quality of life of cancer survivors. Chemotherapy-induced peripheral neuropathy is a frequent side effects of platinum-based chemotherapy agents. This cluster of complications is often so debilitating that patients occasionally have to discontinue the therapy. Sensory neurons of dorsal root ganglia are at the core of chemotherapy-induced peripheral neuropathy symptoms. In these postmitotic cells, DNA damage caused by platinum chemotherapy interferes with normal functioning. Accumulation of DNA-platinum adducts correlates with neurotoxic severity and development of sensation of pain. While biochemistry of DNA-platinum adducts is the same in all cell types, molecular mechanisms affected by DNA-platinum adducts are different in cancer cells and non-dividing cells. This review aims to raise awareness about platinum associated chemotherapy-induced peripheral neuropathy as a medical problem that has remained unexplained for decades. We emphasize the complexity of this condition both from clinical and mechanistical point of view and focus on recent findings about chemotherapy-induced peripheral neuropathy in in vitro and in vivo model systems. Finally, we summarize current perspectives about clinical approaches for chemotherapy-induced peripheral neuropathy treatment.
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Affiliation(s)
- Andrijana Lazic
- Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade, Serbia
| | - Jelena Popović
- Feinberg School of Medicine, Department of Radiation Oncology, Northwestern University, Chicago, IL, USA
| | - Tatjana Paunesku
- Feinberg School of Medicine, Department of Radiation Oncology, Northwestern University, Chicago, IL, USA
| | - Gayle E Woloschak
- Feinberg School of Medicine, Department of Radiation Oncology, Northwestern University, Chicago, IL, USA
| | - Milena Stevanović
- Institute of Molecular Genetics and Genetic Engineering; Faculty of Biology; Serbian Academy of Sciences and Arts, Belgrade, Serbia
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Weaver KR, Melkus GD, Fletcher J, Henderson WA. Relevance of Sex and Subtype in Patients With IBS: An Exploratory Study of Gene Expression. Biol Res Nurs 2020; 22:13-23. [PMID: 31833409 PMCID: PMC7068753 DOI: 10.1177/1099800419889189] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
BACKGROUND Psychological state, stress level, and gastrointestinal function are intricately related and relevant to symptom exacerbation in patients with irritable bowel syndrome (IBS), but genetic contributors to this brain-gut connection are not fully understood. The purpose of this exploratory study was to compare gene expression in participants with IBS to that of healthy controls (HC) and to examine patterns of expression in participants with IBS by sex and IBS subtype. METHOD Participants were recruited to an ongoing protocol at the National Institutes of Health. Differences in demographic and clinical characteristics were assessed using descriptive statistics and Mann-Whitney U tests. Expression levels of 84 genes were evaluated in peripheral whole blood using Custom RT2 Profiler polymerase chain reaction (PCR) Arrays, and data analysis was performed through GeneGlobe Data Analysis Center. RESULTS Participants with IBS (n = 27) reported greater levels of perceived stress (p = .037) and differed in expression values of ±2 for the genes ADIPOR1, ADIPOR2, CNR2, COMT, OXTR, and PPARA compared to HC (n = 43). Further analyses by sex and IBS subtype revealed differential patterns of gene expression related to the endocannabinoid system, cytokines, stress, and sex steroid hormones. CONCLUSIONS Diverse yet interconnected processes such as metabolism, inflammation, immunity, social behavior, and pain are associated with differences in gene expression between participants with IBS and HC. These findings lend support for genomic associations with the brain-gut connection in patients with IBS and highlight the relevance of sex and IBS subtype in performing such analyses.
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Affiliation(s)
- Kristen R. Weaver
- Department of Pain and Translational Symptom Science, University of Maryland
School of Nursing, Baltimore, MD, USA
- National Institute of Nursing Research, National Institutes of Health,
Bethesda, MD, USA
| | | | - Jason Fletcher
- Rory Meyers College of Nursing, New York University, NY, USA
| | - Wendy A. Henderson
- Digestive Disorders Unit, Division of Intramural Research, National
Institute of Nursing Research, National Institutes of Health, Bethesda, MD, USA
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Naseri R, Farzaei F, Fakhri S, El-Senduny FF, Altouhamy M, Bahramsoltani R, Ebrahimi F, Rahimi R, Farzaei MH. Polyphenols for diabetes associated neuropathy: Pharmacological targets and clinical perspective. Daru 2019; 27:781-798. [PMID: 31352568 PMCID: PMC6895369 DOI: 10.1007/s40199-019-00289-w] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2019] [Accepted: 07/01/2019] [Indexed: 12/31/2022] Open
Abstract
OBJECTIVES Diabetic neuropathy (DNP) is a widespread and debilitating complication with complex pathophysiology that is caused by neuronal dysfunction in diabetic patients. Conventional therapeutics for DNP are quite challenging due to their serious adverse effects. Hence, there is a need to investigate novel effective and safe options. The novelty of the present study was to provide available therapeutic approaches, emerging molecular mechanisms, signaling pathways and future directions of DNP as well as polyphenols' effect, which accordingly, give new insights for paving the way for novel treatments in DNP. EVIDENCE ACQUISITION A comprehensive review was done in electronic databases including Medline, PubMed, Web of Science, Scopus, national database (Irandoc and SID), and related articles regarding metabolic pathways on the pathogenesis of DNP as well as the polyphenols' effect. The keywords "diabetic neuropathy" and "diabetes mellitus" in the title/abstract and "polyphenol" in the whole text were used. Data were collected from inception until May 2019. RESULTS DNP complications is mostly related to a poor glycemic control and metabolic imbalances mainly inflammation and oxidative stress. Several signaling and molecular pathways play key roles in the pathogenesis and progression of DNP. Among natural entities, polyphenols are suggested as multi-target alternatives affecting most of these pathogenesis mechanisms in DNP. CONCLUSION The findings revealed novel pathogenicity signaling pathways of DNP and affirmed the auspicious role of polyphenols to tackle these destructive pathways in order to prevent, manage, and treat various diseases. Graphical Abstract .
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Affiliation(s)
- Rozita Naseri
- Faculty of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Fatemeh Farzaei
- Pharmaceutical Sciences Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Sajad Fakhri
- Pharmaceutical Sciences Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Fardous F El-Senduny
- Biochemistry division, Chemistry Department, Faculty of Science, Mansoura University, Mansoura, 35516, Egypt
| | - Miram Altouhamy
- Biochemistry Department, Faculty of Science, Ain Shams University, Cairo, Egypt
| | - Roodabeh Bahramsoltani
- Department of Pharmacy in Persian Medicine, School of Persian Medicine, Tehran University of Medical Sciences, Tehran, Iran
- PhytoPharmacology Interest Group (PPIG), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Farnaz Ebrahimi
- Pharmacy students` research committee, School of pharmacy, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Roja Rahimi
- Department of Pharmacy in Persian Medicine, School of Persian Medicine, Tehran University of Medical Sciences, Tehran, Iran
- PhytoPharmacology Interest Group (PPIG), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Mohammad Hosein Farzaei
- Pharmaceutical Sciences Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran.
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Quintão NLM, Santin JR, Stoeberl LC, Corrêa TP, Melato J, Costa R. Pharmacological Treatment of Chemotherapy-Induced Neuropathic Pain: PPARγ Agonists as a Promising Tool. Front Neurosci 2019; 13:907. [PMID: 31555078 PMCID: PMC6722212 DOI: 10.3389/fnins.2019.00907] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2019] [Accepted: 08/14/2019] [Indexed: 12/24/2022] Open
Abstract
Chemotherapy-induced neuropathic pain (CINP) is one of the most severe side effects of anticancer agents, such as platinum- and taxanes-derived drugs (oxaliplatin, cisplatin, carboplatin and paclitaxel). CINP may even be a factor of interruption of treatment and consequently increasing the risk of death. Besides that, it is important to take into consideration that the incidence of cancer is increasing worldwide, including colorectal, gastric, lung, cervical, ovary and breast cancers, all treated with the aforementioned drugs, justifying the concern of the medical community about the patient’s quality of life. Several physiopathological mechanisms have already been described for CINP, such as changes in axonal transport, mitochondrial damage, increased ion channel activity and inflammation in the central nervous system (CNS). Another less frequent event that may occur after chemotherapy, particularly under oxaliplatin treatment, is the central neurotoxicity leading to disorders such as mental confusion, catatonia, hyporeflexia, etc. To date, no pharmacological therapy has shown satisfactory effect in these cases. In this scenario, duloxetine is the only drug currently in clinical use. Peroxisome proliferator-activated receptors (PPARs) belong to the class of nuclear receptors and are present in several tissues, mainly participating in lipid and glucose metabolism and inflammatory response. There are three PPAR isoforms: α, β/δ and γ. PPARγ, the protagonist of this review, is expressed in adipose tissue, large intestine, spleen and neutrophils. This subtype also plays important role in energy balance, lipid biosynthesis and adipogenesis. The effects of PPARγ agonists, known for their positive activity on type II diabetes mellitus, have been explored and present promising effects in the control of neuropathic pain, including CINP, and also cancer. This review focuses largely on the mechanisms involved in chemotherapy-induced neuropathy and the effects of the activation of PPARγ to treat CINP. It is the aim of this review to help understanding and developing novel CINP therapeutic strategies integrating PPARγ signalling.
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Affiliation(s)
| | | | | | | | - Jéssica Melato
- School of Heath Science, Universidade do Vale do Itajaí, Itajaí, Brazil
| | - Robson Costa
- School of Pharmacy, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.,Wolfson Centre for Age-Related Diseases, King's College London, London, United Kingdom
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Zhou P, Xiang L, Yang Y, Wu Y, Hu T, Liu X, Lin F, Xiu Y, Wu K, Lu C, Ren J, Qiu Y, Li Y. N-Acylethanolamine acid amidase (NAAA) inhibitor F215 as a novel therapeutic agent for osteoarthritis. Pharmacol Res 2019; 145:104264. [PMID: 31063807 DOI: 10.1016/j.phrs.2019.104264] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2019] [Revised: 04/22/2019] [Accepted: 05/03/2019] [Indexed: 12/15/2022]
Abstract
Osteoarthritis (OA), characterized by cartilage damage, synovitis inflammation and chronic pain, is a common degenerative joint disease that may lead to physical disability. In the present study, we first explored the association between N-Acylethanolamine acid amidase (NAAA) and OA progression, and then examined the capability of the NAAA inhibitor F215 to attenuate osteoarthritis. Increased NAAA expressions and decreased PEA levels in synovial membrane and lumbar spinal cord were observed in MIA induced osteoarthritic rats. F215 (i.a., and i.p.) significantly protected against cartilage damage and synovial inflammation by directly increasing PEA levels in joints, or normalization of PEA levels and resolution of inflammation in spinal cord. Moreover, F215 also markedly alleviated osteoarthritic pain in rats, and the therapeutic effects of F215 were blocked by the PPAR-α antagonist MK886. The results revealed that NAAA may has been implicated in OA progression, and treatment with NAAA inhibitor F215 alleviated OA development by preventing cartilage damage, reducing inflammation, and alleviating pain. Our study suggested that NAAA inhibitor might be a novel therapeutic agent for OA treatment.
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Affiliation(s)
- Pan Zhou
- Eye Institute of Xiamen University, Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, School of Medicine, Xiamen University, Xiamen, 361102, China; Department of Ophthalmology, Xiang'an Hospital of Xiamen University, Xiamen, 361102, China
| | - Lei Xiang
- Eye Institute of Xiamen University, Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, School of Medicine, Xiamen University, Xiamen, 361102, China
| | - Yulong Yang
- Eye Institute of Xiamen University, Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, School of Medicine, Xiamen University, Xiamen, 361102, China
| | - Yuezhou Wu
- Eye Institute of Xiamen University, Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, School of Medicine, Xiamen University, Xiamen, 361102, China
| | - Ting Hu
- Xiamen Institute of Rare-earth Materials, Haixi Institutes, Chinese Academy of Sciences, Fujian, 361005, China
| | - Xiaolong Liu
- Xiamen Institute of Rare-earth Materials, Haixi Institutes, Chinese Academy of Sciences, Fujian, 361005, China
| | - Feitai Lin
- Department of Joint, Xiamen University Affiliated Second Hospital of Fuzhou, Fujian, 361000, China
| | - Yanghui Xiu
- Xiamen University affiliated Xiamen Eye Center, Xiamen, 361005, China
| | - Kangni Wu
- The First Affiliated Hospital of Xiamen University, Xiamen, 361003, China
| | - Canzhong Lu
- Xiamen Institute of Rare-earth Materials, Haixi Institutes, Chinese Academy of Sciences, Fujian, 361005, China
| | - Jie Ren
- Eye Institute of Xiamen University, Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, School of Medicine, Xiamen University, Xiamen, 361102, China; Department of Ophthalmology, Xiang'an Hospital of Xiamen University, Xiamen, 361102, China
| | - Yan Qiu
- Eye Institute of Xiamen University, Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, School of Medicine, Xiamen University, Xiamen, 361102, China; Department of Ophthalmology, Xiang'an Hospital of Xiamen University, Xiamen, 361102, China.
| | - Yuhang Li
- Xiamen Institute of Rare-earth Materials, Haixi Institutes, Chinese Academy of Sciences, Fujian, 361005, China.
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Abstract
LINKED ARTICLES This article is part of a themed section on 8th European Workshop on Cannabinoid Research. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.10/issuetoc.
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Abstract
Substance P (SP) is a highly conserved member of the tachykinin peptide family that is widely expressed throughout the animal kingdom. The numerous members of the tachykinin peptide family are involved in a multitude of neuronal signaling pathways, mediating sensations and emotional responses (Steinhoff et al. in Physiol Rev 94:265–301, 2014). In contrast to receptors for classical transmitters, such as glutamate (Parsons et al. in Handb Exp Pharmacol 249–303, 2005), only a minority of neurons in certain brain areas express neurokinin receptors (NKRs) (Mantyh in J Clin Psychiatry 63:6–10, 2002). SP is also expressed by a variety of non-neuronal cell types such as microglia, as well as immune cells (Mashaghi et al. in Cell Mol Life Sci 73:4249–4264, 2016). SP is an 11-amino acid neuropeptide that preferentially activates the neurokinin-1 receptor (NK1R). It transmits nociceptive signals via primary afferent fibers to spinal and brainstem second-order neurons (Cao et al. in Nature 392:390–394, 1998). Compounds that inhibit SP’s action are being investigated as potential drugs to relieve pain. More recently, SP and NKR have gained attention for their role in complex psychiatric processes. It is a key goal in the field of pain research to understand mechanisms involved in the transition between acute pain and chronic pain. The influence of emotional and cognitive inputs and feedbacks from different brain areas makes pain not only a perception but an experience (Zieglgänsberger et al. in CNS Spectr 10:298–308, 2005; Trenkwaldner et al. Sleep Med 31:78–85, 2017). This review focuses on functional neuronal plasticity in spinal dorsal horn neurons as a major relay for nociceptive information.
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Okine BN, Gaspar JC, Finn DP. PPARs and pain. Br J Pharmacol 2018; 176:1421-1442. [PMID: 29679493 DOI: 10.1111/bph.14339] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2017] [Revised: 02/19/2018] [Accepted: 03/26/2018] [Indexed: 02/06/2023] Open
Abstract
Chronic pain is a common cause of disability worldwide and remains a global health and socio-economic challenge. Current analgesics are either ineffective in a significant proportion of patients with chronic pain or associated with significant adverse side effects. The PPARs, a family of nuclear hormone transcription factors, have emerged as important modulators of pain in preclinical studies and therefore a potential therapeutic target for the treatment of pain. Modulation of nociceptive processing by PPARs is likely to involve both transcription-dependent and transcription-independent mechanisms. This review presents a comprehensive overview of preclinical studies investigating the contribution of PPAR signalling to nociceptive processing in animal models of inflammatory and neuropathic pain. We examine current evidence from anatomical, molecular and pharmacological studies demonstrating a role for PPARs in pain control. We also discuss the limited evidence available from relevant clinical studies and identify areas that warrant further research. LINKED ARTICLES: This article is part of a themed section on 8th European Workshop on Cannabinoid Research. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.10/issuetoc.
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Affiliation(s)
- Bright N Okine
- Pharmacology and Therapeutics, National University of Ireland Galway, Galway, Ireland.,Galway Neuroscience Centre, National University of Ireland Galway, Galway, Ireland.,Centre for Pain Research, NCBES, National University of Ireland Galway, Galway, Ireland
| | - Jessica C Gaspar
- Pharmacology and Therapeutics, National University of Ireland Galway, Galway, Ireland.,Galway Neuroscience Centre, National University of Ireland Galway, Galway, Ireland.,Centre for Pain Research, NCBES, National University of Ireland Galway, Galway, Ireland
| | - David P Finn
- Pharmacology and Therapeutics, National University of Ireland Galway, Galway, Ireland.,Galway Neuroscience Centre, National University of Ireland Galway, Galway, Ireland.,Centre for Pain Research, NCBES, National University of Ireland Galway, Galway, Ireland
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