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Ozer EA, Keskin A, Berrak YH, Cankara F, Can F, Gursoy-Ozdemir Y, Keskin O, Gursoy A, Yapici-Eser H. Shared interactions of six neurotropic viruses with 38 human proteins: a computational and literature-based exploration of viral interactions and hijacking of human proteins in neuropsychiatric disorders. DISCOVER MENTAL HEALTH 2025; 5:18. [PMID: 39987419 PMCID: PMC11846830 DOI: 10.1007/s44192-025-00128-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/07/2024] [Accepted: 01/09/2025] [Indexed: 02/24/2025]
Abstract
INTRODUCTION Viral infections may disrupt the structural and functional integrity of the nervous system, leading to acute conditions such as encephalitis, and neuropsychiatric conditions as mood disorders, schizophrenia, and neurodegenerative diseases. Investigating viral interactions of human proteins may reveal mechanisms underlying these effects and offer insights for therapeutic interventions. This study explores molecular interactions of virus and human proteins that may be related to neuropsychiatric disorders. METHODS Herpes Simplex Virus-1 (HSV-1), Cytomegalovirus (CMV), Epstein-Barr Virus (EBV), Influenza A virus (IAV) (H1N1, H5N1), and Human Immunodeficiency Virus (HIV1&2) were selected as key viruses. Protein structures for each virus were accessed from the Protein Data Bank and analyzed using the HMI-Pred web server to detect interface mimicry between viral and human proteins. The PANTHER classification system was used to categorize viral-human protein interactions based on function and cellular localization. RESULTS Energetically favorable viral-human protein interactions were identified for HSV-1 (467), CMV (514), EBV (495), H1N1 (3331), H5N1 (3533), and HIV 1&2 (62425). Besides immune and apoptosis-related pathways, key neurodegenerative pathways, including those associated with Parkinson's and Huntington's diseases, were frequently interacted. A total of 38 human proteins, including calmodulin 2, Ras-related botulinum toxin substrate 1 (Rac1), PDGF-β, and vimentin, were found to interact with all six viruses. CONCLUSION The study indicates a substantial number of energetically favorable interactions between human proteins and selected viral proteins, underscoring the complexity and breadth of viral strategies to hijack host cellular mechanisms. Further in vivo and in vitro validation is required to understand the implications of these interactions.
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Affiliation(s)
| | - Aleyna Keskin
- School of Medicine, Koç University, Istanbul, Turkey
| | | | - Fatma Cankara
- Graduate School of Sciences and Engineering, Computational Sciences and Engineering, Koç University, Istanbul, Turkey
| | - Fusun Can
- Department of Microbiology, School of Medicine, Koç University, Istanbul, Turkey
| | - Yasemin Gursoy-Ozdemir
- Department of Neurology, School of Medicine, Koç University, Istanbul, Turkey
- Research Center for Translational Medicine (KUTTAM), Koç University, Istanbul, Turkey
| | - Ozlem Keskin
- Department of Chemical and Biological Engineering, College of Engineering, Koç University, Istanbul, Turkey
| | - Attila Gursoy
- Department of Computer Science and Engineering, College of Engineering, Koç University, Istanbul, Turkey.
| | - Hale Yapici-Eser
- Research Center for Translational Medicine (KUTTAM), Koç University, Istanbul, Turkey.
- Department of Psychiatry, School of Medicine, Koç University, Istanbul, Turkey.
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Banks WA, Rhea EM, Reed MJ, Erickson MA. The penetration of therapeutics across the blood-brain barrier: Classic case studies and clinical implications. Cell Rep Med 2024; 5:101760. [PMID: 39383873 PMCID: PMC11604479 DOI: 10.1016/j.xcrm.2024.101760] [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: 04/12/2024] [Revised: 06/20/2024] [Accepted: 09/11/2024] [Indexed: 10/11/2024]
Abstract
The blood-brain barrier (BBB) plays central roles in the maintenance and health of the brain. Its mechanisms to safeguard the brain against xenobiotics and endogenous toxins also make the BBB the primary obstacle to the development of drugs for the central nervous system (CNS). Here, we review classic examples of the intersection of clinical medicine, drug delivery, and the BBB. We highlight the role of lipid solubility (heroin), saturable brain-to-blood (efflux: opiates) and blood-to-brain (influx: nutrients, vitamins, and minerals) transport systems, and adsorptive transcytosis (viruses and incretin receptor agonists). We examine how the disruption of the BBB that occurs in certain diseases (tumors) can also be modulated (osmotic agents and microbubbles) and used to deliver treatments, and the role of extracellular pathways in gaining access to the CNS (albumin and antibodies). In summary, this review provides a historical perspective of the key role of the BBB in delivery of drugs to the brain in health and disease.
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Affiliation(s)
- William A Banks
- Geriatric Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108, USA; Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington School of Medicine, Seattle, WA 98104, USA.
| | - Elizabeth M Rhea
- Geriatric Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108, USA; Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington School of Medicine, Seattle, WA 98104, USA
| | - May J Reed
- Geriatric Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108, USA; Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington School of Medicine, Seattle, WA 98104, USA
| | - Michelle A Erickson
- Geriatric Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108, USA; Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington School of Medicine, Seattle, WA 98104, USA
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Alagiakrishnan K, Halverson T. Role of Peripheral and Central Insulin Resistance in Neuropsychiatric Disorders. J Clin Med 2024; 13:6607. [PMID: 39518747 PMCID: PMC11547162 DOI: 10.3390/jcm13216607] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2024] [Revised: 10/27/2024] [Accepted: 10/31/2024] [Indexed: 11/16/2024] Open
Abstract
Insulin acts on different organs, including the brain, which helps it regulate energy metabolism. Insulin signaling plays an important role in the function of different cell types. In this review, we have summarized the key roles of insulin and insulin receptors in healthy brains and in different brain disorders. Insulin signaling, as well as insulin resistance (IR), is a major contributor in the regulation of mood, behavior, and cognition. Recent evidence showed that both peripheral and central insulin resistance play a role in the pathophysiology, clinical presentation, and management of neuropsychiatric disorders like Cognitive Impairment/Dementia, Depression, and Schizophrenia. Many human studies point out Insulin Resistance/Metabolic Syndrome can increase the risk of dementia especially Alzheimer's dementia (AD). IR has been shown to play a role in AD development but also in its progression. This review article discusses the pathophysiological pathways and mechanisms of insulin resistance in major neuropsychiatric disorders. The extent of insulin resistance can be quantified using IR biomarkers like insulin levels, HOMA-IR index, and Triglyceride glucose-body mass index (TyG-BMI) levels. IR has been shown to precede neurodegeneration. Human trials showed current treatment with certain antidiabetic drugs, as well as life style management, like weight loss and exercise for IR, have shown promise in the management of cognitive/neuropsychiatric disorders. This may pave the pathway to the development of new therapeutic approaches to these challenging disorders of dementia and psychiatric diseases. Recent clinical trials are showing some encouraging evidence for these pharmacological and nonpharmacological approaches for IR in psychiatric and cognitive disorders, even though more research is needed to apply this evidence into clinical practice. Early identification and management of IR may help as a strategy to potentially alter neuropsychiatric disorders onset as well as its progression.
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Affiliation(s)
| | - Tyler Halverson
- Department of Psychiatry, University of Toronto, Toronto, ON M5T 1R8, Canada;
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4
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Cheng X, Tan Y, Li H, Zhang Z, Hui S, Zhang Z, Peng W. Mechanistic Insights and Potential Therapeutic Implications of NRF2 in Diabetic Encephalopathy. Mol Neurobiol 2024; 61:8253-8278. [PMID: 38483656 DOI: 10.1007/s12035-024-04097-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Accepted: 03/04/2024] [Indexed: 09/21/2024]
Abstract
Diabetic encephalopathy (DE) is a complication of diabetes, especially type 2 diabetes (T2D), characterized by damage in the central nervous system and cognitive impairment, which has gained global attention. Despite the extensive research aimed at enhancing our understanding of DE, the underlying mechanism of occurrence and development of DE has not been established. Mounting evidence has demonstrated a close correlation between DE and various factors, such as Alzheimer's disease-like pathological changes, insulin resistance, inflammation, and oxidative stress. Of interest, nuclear factor erythroid 2-related factor 2 (NRF2) is a transcription factor with antioxidant properties that is crucial in maintaining redox homeostasis and regulating inflammatory responses. The activation and regulatory mechanisms of NRF2 are a relatively complex process. NRF2 is involved in the regulation of multiple metabolic pathways and confers neuroprotective functions. Multiple studies have provided evidence demonstrating the significant involvement of NRF2 as a critical transcription factor in the progression of DE. Additionally, various molecules capable of activating NRF2 expression have shown potential in ameliorating DE. Therefore, it is intriguing to consider NRF2 as a potential target for the treatment of DE. In this review, we aim to shed light on the role and the possible underlying mechanism of NRF2 in DE. Furthermore, we provide an overview of the current research landscape and address the challenges associated with using NRF2 activators as potential treatment options for DE.
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Affiliation(s)
- Xin Cheng
- Department of Integrated Traditional Chinese & Western Medicine, The Second Xiangya Hospital, Central South University, No.139 Middle Renmin Road, Changsha, Hunan, 410011, People's Republic of China
- National Clinical Research Center for Mental Disorder, Changsha, 410011, China
| | - Yejun Tan
- School of Mathematics, University of Minnesota, Twin Cities, Minneapolis, MN, USA
| | - Hongli Li
- Department of Integrated Traditional Chinese & Western Medicine, The Second Xiangya Hospital, Central South University, No.139 Middle Renmin Road, Changsha, Hunan, 410011, People's Republic of China
- National Clinical Research Center for Mental Disorder, Changsha, 410011, China
| | - Zhen Zhang
- YangSheng College of Traditional Chinese Medicine, Guizhou University of Traditional Chinese Medicine, Guiyang, 550025, Guizhou, China
| | - Shan Hui
- Department of Geratology, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, 410005, China
| | - Zheyu Zhang
- Department of Integrated Traditional Chinese & Western Medicine, The Second Xiangya Hospital, Central South University, No.139 Middle Renmin Road, Changsha, Hunan, 410011, People's Republic of China.
- National Clinical Research Center for Mental Disorder, Changsha, 410011, China.
| | - Weijun Peng
- Department of Integrated Traditional Chinese & Western Medicine, The Second Xiangya Hospital, Central South University, No.139 Middle Renmin Road, Changsha, Hunan, 410011, People's Republic of China.
- National Clinical Research Center for Mental Disorder, Changsha, 410011, China.
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Affuso F, Micillo F, Fazio S. Insulin Resistance, a Risk Factor for Alzheimer's Disease: Pathological Mechanisms and a New Proposal for a Preventive Therapeutic Approach. Biomedicines 2024; 12:1888. [PMID: 39200352 PMCID: PMC11351221 DOI: 10.3390/biomedicines12081888] [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: 06/12/2024] [Revised: 07/31/2024] [Accepted: 08/13/2024] [Indexed: 09/02/2024] Open
Abstract
Peripheral insulin resistance (IR) is a well-documented, independent risk factor for the development of type 2 diabetes, cardiovascular disease, cancer and cellular senescence. Recently, the brain has also been identified as an insulin-responsive region, where insulin acts as regulator of the brain metabolism. Despite the clear link between IR and the brain, the exact mechanisms underlying this relationship remain unclear. Therapeutic intervention in patients showing symptoms of neurodegenerative diseases has produced little or no results. It has been demonstrated that insulin resistance plays a significant role in the pathogenesis of neurodegenerative diseases, particularly cognitive decline. Peripheral and brain IR may represent a modifiable state that could be used to prevent major brain disorders. In this review, we will analyse the scientific literature supporting IR as a risk factor for Alzheimer's disease and suggest some therapeutic strategies to provide a new proposal for the prevention of brain IR and its consequences.
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Affiliation(s)
- Flora Affuso
- Independent Researcher, Viale Raffaello, 74, 80129 Napoli, Italy
| | - Filomena Micillo
- UOC of Geriatric Medicine AORN S.G. Moscati, 83100 Avellino, Italy
| | - Serafino Fazio
- Department of Internal Medicine, School of Medicine, Federico II University of Naples, 80138 Naples, Italy;
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Chaklai A, Rhea EM, O'Niel A, Babin A, Weaver R, Pemberton S, Banks WA, Raber J. Effects of a high-fat diet on cognition and brain distribution of intranasal insulin in E3 and E4 male and female mice. Sci Rep 2024; 14:18641. [PMID: 39128931 PMCID: PMC11317510 DOI: 10.1038/s41598-024-62053-8] [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: 03/05/2024] [Accepted: 05/08/2024] [Indexed: 08/13/2024] Open
Abstract
There are genetic and environmental risk factors that contribute to the development of cognitive decline in Alzheimer's disease (AD). Some of these include the genetic predisposition of the apolipoprotein E4 genotype, consuming a high-fat diet (HFD), and the female sex. Brain insulin receptor resistance and deficiency have also been shown to be associated with AD and cognitive impairment. Intranasal (INL) insulin enhances cognition in AD, but the response varies due to genotype, diet, and sex. We investigated here the combination of these risk factors in a humanized mouse model, expressing E3 or E4, following a HFD in males and females on cognitive performance and the brain distribution of insulin following INL delivery. The HFD had a negative effect on survival in male mice only, requiring sex to be collapsed. We found many genotype, diet, and genotype x diet effects in anxiety-related tasks. We further found beneficial effects of INL insulin in our memory tests, with the most important findings showing a beneficial effect of INL insulin in mice on a HFD. We found insulin distribution throughout the brain after INL delivery was largely unaffected by diet and genotype, indicating these susceptible groups can still receive adequate levels of insulin following INL delivery. Our findings support the involvement of brain insulin signaling in cognition and highlight continuing efforts investigating mechanisms resulting from treatment with INL insulin.
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Affiliation(s)
- Ariel Chaklai
- Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR, 97239, USA
| | - Elizabeth M Rhea
- Geriatric Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA, 98108, USA
- Department of Medicine, University of Washington, Seattle, WA, 98195, USA
| | - Abigail O'Niel
- Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR, 97239, USA
| | - Alice Babin
- Geriatric Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA, 98108, USA
| | - Riley Weaver
- Geriatric Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA, 98108, USA
| | - Sarah Pemberton
- Geriatric Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA, 98108, USA
| | - William A Banks
- Geriatric Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA, 98108, USA
- Department of Medicine, University of Washington, Seattle, WA, 98195, USA
| | - Jacob Raber
- Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR, 97239, USA.
- Division of Neuroscience, Departments of Neurology and Radiation Medicine, ONPRC, Oregon Health & Science University, Portland, OR, 97239, USA.
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7
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Rhea EM, Leclerc M, Yassine HN, Capuano AW, Tong H, Petyuk VA, Macauley SL, Fioramonti X, Carmichael O, Calon F, Arvanitakis Z. State of the Science on Brain Insulin Resistance and Cognitive Decline Due to Alzheimer's Disease. Aging Dis 2024; 15:1688-1725. [PMID: 37611907 PMCID: PMC11272209 DOI: 10.14336/ad.2023.0814] [Citation(s) in RCA: 14] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2023] [Accepted: 08/14/2023] [Indexed: 08/25/2023] Open
Abstract
Type 2 diabetes mellitus (T2DM) is common and increasing in prevalence worldwide, with devastating public health consequences. While peripheral insulin resistance is a key feature of most forms of T2DM and has been investigated for over a century, research on brain insulin resistance (BIR) has more recently been developed, including in the context of T2DM and non-diabetes states. Recent data support the presence of BIR in the aging brain, even in non-diabetes states, and found that BIR may be a feature in Alzheimer's disease (AD) and contributes to cognitive impairment. Further, therapies used to treat T2DM are now being investigated in the context of AD treatment and prevention, including insulin. In this review, we offer a definition of BIR, and present evidence for BIR in AD; we discuss the expression, function, and activation of the insulin receptor (INSR) in the brain; how BIR could develop; tools to study BIR; how BIR correlates with current AD hallmarks; and regional/cellular involvement of BIR. We close with a discussion on resilience to both BIR and AD, how current tools can be improved to better understand BIR, and future avenues for research. Overall, this review and position paper highlights BIR as a plausible therapeutic target for the prevention of cognitive decline and dementia due to AD.
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Affiliation(s)
- Elizabeth M Rhea
- Geriatric Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108, USA.
- Department of Medicine, Division of Gerontology and Geriatric Medicine, University of Washington, Seattle, WA 98195, USA.
| | - Manon Leclerc
- Faculty of Pharmacy, Laval University, Quebec, Quebec, Canada.
- Neuroscience Axis, CHU de Québec Research Center - Laval University, Quebec, Quebec, Canada.
| | - Hussein N Yassine
- Departments of Neurology and Medicine, University of Southern California, Los Angeles, CA 90033, USA.
| | - Ana W Capuano
- Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, IL 60612, USA.
| | - Han Tong
- Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, IL 60612, USA.
| | - Vladislav A Petyuk
- Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA 99352, USA.
| | - Shannon L Macauley
- Department of Physiology, University of Kentucky, Lexington, KY 40508, USA.
| | - Xavier Fioramonti
- International Associated Laboratory OptiNutriBrain, Bordeaux, France and Quebec, Canada.
- Univ. Bordeaux, INRAE, Bordeaux INP, NutriNeuro, UMR 1286, F-33000 Bordeaux, France.
| | - Owen Carmichael
- Pennington Biomedical Research Center, Baton Rouge, LA 70808, USA.
| | - Frederic Calon
- Faculty of Pharmacy, Laval University, Quebec, Quebec, Canada.
- Neuroscience Axis, CHU de Québec Research Center - Laval University, Quebec, Quebec, Canada.
- International Associated Laboratory OptiNutriBrain, Bordeaux, France and Quebec, Canada.
| | - Zoe Arvanitakis
- Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, IL 60612, USA.
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Afridi R, Kim JH, Bhusal A, Lee WH, Suk K. Lipocalin-2 as a mediator of neuroimmune communication. J Leukoc Biol 2024; 116:357-368. [PMID: 38149462 DOI: 10.1093/jleuko/qiad157] [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: 10/06/2023] [Revised: 11/16/2023] [Accepted: 11/22/2023] [Indexed: 12/28/2023] Open
Abstract
Lipocalin-2, a neutrophil gelatinase-associated lipocalin, is a 25-kDa secreted protein implicated in a broad range of inflammatory diseases affecting the brain and periphery. It is a pleotropic protein expressed by various immune and nonimmune cells throughout the body. Importantly, the surge in lipocalin-2 levels in disease states has been associated with a myriad of undesirable effects, further exacerbating the ongoing pathological processes. In the brain, glial cells are the principal source of lipocalin-2, which plays a definitive role in determining their functional phenotypes. In different central nervous system pathologies, an increased expression of glial lipocalin-2 has been linked to neurotoxicity. Lipocalin-2 mediates a crosstalk between central and peripheral immune cells under neuroinflammatory conditions. One intriguing aspect is that elevated lipocalin-2 levels in peripheral disorders, such as cancer, metabolic conditions, and liver diseases, potentially incite an inflammatory activation of glial cells while disrupting neuronal functions. This review comprehensively summarizes the influence of lipocalin-2 on the exacerbation of neuroinflammation by regulating various cellular processes. Additionally, this review explores lipocalin-2 as a mediator of neuroimmune crosstalk in various central nervous system pathologies and highlights the role of lipocalin-2 in carrying inflammatory signals along the neuroimmune axis.
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Affiliation(s)
- Ruqayya Afridi
- Department of Pharmacology, School of Medicine, Kyungpook National University, 680 Gukchaebosang Street, Joong-gu, Daegu 41944, Republic of Korea
- Brain Korea 21 four KNU Convergence Educational Program of Biomedical Sciences for Creative Future Talents, Kyungpook National University, 680 Gukchaebosang Street, Joong-gu, Daegu 41940, Republic of Korea
| | - Jae-Hong Kim
- Department of Pharmacology, School of Medicine, Kyungpook National University, 680 Gukchaebosang Street, Joong-gu, Daegu 41944, Republic of Korea
- Brain Korea 21 four KNU Convergence Educational Program of Biomedical Sciences for Creative Future Talents, Kyungpook National University, 680 Gukchaebosang Street, Joong-gu, Daegu 41940, Republic of Korea
| | - Anup Bhusal
- Department of Pharmacology, School of Medicine, Kyungpook National University, 680 Gukchaebosang Street, Joong-gu, Daegu 41944, Republic of Korea
- Brain Korea 21 four KNU Convergence Educational Program of Biomedical Sciences for Creative Future Talents, Kyungpook National University, 680 Gukchaebosang Street, Joong-gu, Daegu 41940, Republic of Korea
| | - Won-Ha Lee
- School of Life Sciences, BK21 plus KNU Creative BioResearch Group, Kyungpook National University, 80 Daehak-ro, Buk-gu, Daegu 41566, Republic of Korea
- Brain Science and Engineering Institute, Kyungpook National University, 680 Gukchaebosang Street, Joong-gu, Daegu 41944, Republic of Korea
| | - Kyoungho Suk
- Department of Pharmacology, School of Medicine, Kyungpook National University, 680 Gukchaebosang Street, Joong-gu, Daegu 41944, Republic of Korea
- Brain Korea 21 four KNU Convergence Educational Program of Biomedical Sciences for Creative Future Talents, Kyungpook National University, 680 Gukchaebosang Street, Joong-gu, Daegu 41940, Republic of Korea
- Brain Science and Engineering Institute, Kyungpook National University, 680 Gukchaebosang Street, Joong-gu, Daegu 41944, Republic of Korea
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McMillan NJ, Jacob DW, Shariffi B, Harper JL, Foster GE, Manrique-Acevedo C, Padilla J, Limberg JK. Effect of acute intranasal insulin administration on muscle sympathetic nerve activity in healthy young adults. Am J Physiol Heart Circ Physiol 2024; 327:H000. [PMID: 38787381 PMCID: PMC11390129 DOI: 10.1152/ajpheart.00253.2024] [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: 04/22/2024] [Revised: 05/14/2024] [Accepted: 05/23/2024] [Indexed: 05/25/2024]
Abstract
Systemic insulin increases muscle sympathetic nerve activity (MSNA) via both central actions within the brainstem and peripheral activation of the arterial baroreflex. Augmented MSNA during hyperinsulinemia likely restrains peripheral vasodilation and contributes to the maintenance of blood pressure (BP). However, in the absence of insulin action within the peripheral vasculature, whether central insulin stimulation increases MSNA and influences peripheral hemodynamics in humans remains unknown. Herein, we hypothesized intranasal insulin administration would increase MSNA and BP in healthy young adults. Participants were assigned to time control [TC, n = 13 (5 females/8 males), 28 ± 1 yr] or 160 IU of intranasal insulin administered over 5 min [n = 15 (5 females/10 males), 26 ± 2 yr]; five (1 female/4 males) participants completed both conditions. MSNA (fibular microneurography), BP (finger photoplethysmography), and leg blood flow (LBF, femoral Doppler ultrasound) were assessed at baseline, and 15 and 30 min following insulin administration. Leg vascular conductance [LVC = (LBF ÷ mean BP) × 100] was calculated. Venous insulin and glucose concentrations remained unchanged throughout (P > 0.05). Following intranasal insulin administration, MSNA (burst frequency; baseline = 100%; minute 15, 121 ± 8%; minute 30, 118 ± 6%; P = 0.009, n = 7) and mean BP (baseline = 100%; minute 15, 103 ± 1%; minute 30, 102 ± 1%; P = 0.003) increased, whereas LVC decreased (baseline = 100%; minute 15, 93 ± 3%; minute 30, 99 ± 3%; P = 0.03). In contrast, MSNA, mean BP, and LVC were unchanged in TC participants (P > 0.05). We provide the first evidence that intranasal insulin administration in healthy young adults acutely increases MSNA and BP and decreases LVC. These results enhance mechanistic understanding of the sympathetic and peripheral hemodynamic response to insulin.NEW & NOTEWORTHY Systemic insulin increases muscle sympathetic nerve activity (MSNA) via central actions within the brainstem and peripheral activation of the arterial baroreflex. In the absence of peripheral insulin action, whether central insulin stimulation increases MSNA and influences peripheral hemodynamics in humans was unknown. We provide the first evidence that intranasal insulin administration increases MSNA and blood pressure and reduces leg vascular conductance. These results enhance mechanistic understanding of the sympathetic and hemodynamic response to insulin.
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Affiliation(s)
- Neil J McMillan
- Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, Missouri, United States
- NextGen Precision Health, University of Missouri, Columbia, Missouri, United States
| | - Dain W Jacob
- Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, Missouri, United States
| | - Brian Shariffi
- Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, Missouri, United States
| | - Jennifer L Harper
- Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, Missouri, United States
| | - Glen E Foster
- School of Health and Exercise Sciences, Centre for Heart, Lung, and Vascular Health, University of British Columbia, Kelowna, Canada
| | - Camila Manrique-Acevedo
- NextGen Precision Health, University of Missouri, Columbia, Missouri, United States
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Missouri, Columbia, Missouri, United States
- Research Services, Harry S. Truman Memorial Veterans Hospital, Columbia, Missouri, United States
| | - Jaume Padilla
- Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, Missouri, United States
- NextGen Precision Health, University of Missouri, Columbia, Missouri, United States
- Research Services, Harry S. Truman Memorial Veterans Hospital, Columbia, Missouri, United States
| | - Jacqueline K Limberg
- Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, Missouri, United States
- Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri, United States
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Gladding JM, Rafiei N, Mitchell CS, Begg DP. Excision of the endothelial blood-brain barrier insulin receptor does not alter spatial cognition in mice fed either a chow or high-fat diet. Neurobiol Learn Mem 2024; 212:107938. [PMID: 38772444 DOI: 10.1016/j.nlm.2024.107938] [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: 12/21/2023] [Revised: 05/02/2024] [Accepted: 05/15/2024] [Indexed: 05/23/2024]
Abstract
Insulin is transported across the blood-brain barrier (BBB) endothelium to regulate aspects of metabolism and cognition. Brain insulin resistance often results from high-fat diet (HFD) consumption and is thought to contribute to spatial cognition deficits. To target BBB insulin function, we used Cre-LoxP genetic excision of the insulin receptor (InsR) from endothelial cells in adult male mice. We hypothesized that this excision would impair spatial cognition, and that high-fat diet consumption would exacerbate these effects. Excision of the endothelial InsR did not impair performance in two spatial cognition tasks, the Y-Maze and Morris Water Maze, in tests held both before and after 14 weeks of access to high-fat (or chow control) diet. The HFD increased body weight gain and induced glucose intolerance but did not impair spatial cognition. Endothelial InsR excision tended to increase body weight and reduce sensitivity to peripheral insulin, but these metabolic effects were not associated with impairments to spatial cognition and did not interact with HFD exposure. Instead, all mice showed intact spatial cognitive performance regardless of whether they had been fed chow or a HFD, and whether the InsR had been excised or not. Overall, the results indicate that loss of the endothelial InsR does not impact spatial cognition, which is in line with pharmacological evidence that other mechanisms at the BBB facilitate insulin transport and allow it to exert its pro-cognitive effects.
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Affiliation(s)
- Joanne M Gladding
- School of Psychology, Faculty of Science, University of New South Wales, Australia.
| | - Neda Rafiei
- School of Psychology, Faculty of Science, University of New South Wales, Australia
| | - Caitlin S Mitchell
- School of Psychology, Faculty of Science, University of New South Wales, Australia
| | - Denovan P Begg
- School of Psychology, Faculty of Science, University of New South Wales, Australia
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11
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Li X, Yang Y, Bai X, Wang X, Tan H, Chen Y, Zhu Y, Liu Q, Wu MN, Li Y. A brain-derived insulin signal encodes protein satiety for nutrient-specific feeding inhibition. Cell Rep 2024; 43:114282. [PMID: 38795342 PMCID: PMC11220824 DOI: 10.1016/j.celrep.2024.114282] [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: 08/25/2023] [Revised: 04/08/2024] [Accepted: 05/10/2024] [Indexed: 05/27/2024] Open
Abstract
The suppressive effect of insulin on food intake has been documented for decades. However, whether insulin signals can encode a certain type of nutrients to regulate nutrient-specific feeding behavior remains elusive. Here, we show that in female Drosophila, a pair of dopaminergic neurons, tritocerebrum 1-dopaminergic neurons (T1-DANs), are directly activated by a protein-intake-induced insulin signal from insulin-producing cells (IPCs). Intriguingly, opto-activating IPCs elicits feeding inhibition for both protein and sugar, while silencing T1-DANs blocks this inhibition only for protein food. Elevating insulin signaling in T1-DANs or opto-activating these neurons is sufficient to mimic protein satiety. Furthermore, this signal is conveyed to local neurons of the protocerebral bridge (PB-LNs) and specifically suppresses protein intake. Therefore, our findings reveal that a brain-derived insulin signal encodes protein satiety and suppresses feeding behavior in a nutrient-specific manner, shedding light on the functional specificity of brain insulin signals in regulating behaviors.
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Affiliation(s)
- Xiaoyu Li
- Institute of Biophysics, State Key Laboratory of Brain and Cognitive Science, Center for Excellence in Biomacromolecules, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Yang Yang
- Institute of Biophysics, State Key Laboratory of Brain and Cognitive Science, Center for Excellence in Biomacromolecules, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Xiaobing Bai
- Institute of Biophysics, State Key Laboratory of Brain and Cognitive Science, Center for Excellence in Biomacromolecules, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China; Sino-Danish Center for Education and Research, Beijing 100190, China
| | - Xiaotong Wang
- Institute of Biophysics, State Key Laboratory of Brain and Cognitive Science, Center for Excellence in Biomacromolecules, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Houqi Tan
- Institute of Biophysics, State Key Laboratory of Brain and Cognitive Science, Center for Excellence in Biomacromolecules, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Yanbo Chen
- Institute of Biophysics, State Key Laboratory of Brain and Cognitive Science, Center for Excellence in Biomacromolecules, Chinese Academy of Sciences, Beijing 100101, China
| | - Yan Zhu
- Institute of Biophysics, State Key Laboratory of Brain and Cognitive Science, Center for Excellence in Biomacromolecules, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China; Sino-Danish Center for Education and Research, Beijing 100190, China
| | - Qili Liu
- Department of Anatomy, University of California, San Francisco, San Francisco, CA 94158, USA
| | - Mark N Wu
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Yan Li
- Institute of Biophysics, State Key Laboratory of Brain and Cognitive Science, Center for Excellence in Biomacromolecules, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China; Sino-Danish Center for Education and Research, Beijing 100190, China.
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12
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Ohtsuki S. Insulin receptor at the blood-brain barrier: Transport and signaling. VITAMINS AND HORMONES 2024; 126:113-124. [PMID: 39029970 DOI: 10.1016/bs.vh.2024.05.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/21/2024]
Abstract
The blood-brain barrier (BBB) is a unique system of the brain microvasculature that limits the exchange between the blood and the brain. Brain microvascular endothelial cells form the BBB as part of the neurovascular unit and express insulin receptors. The insulin receptor at the BBB has been studied in two different functional aspects. These functions include (1) the supplying of blood insulin to the brain and (2) the modulation of BBB function via insulin signaling. The first function involves drug delivery to the brain, while the second function is related to the association between central nervous system diseases and type 2 diabetes through insulin resistance. This chapter summarizes recent progress in research on the function of insulin receptors at the BBB.
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Affiliation(s)
- Sumio Ohtsuki
- Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
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13
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Shen J, Wang X, Wang M, Zhang H. Potential molecular mechanism of exercise reversing insulin resistance and improving neurodegenerative diseases. Front Physiol 2024; 15:1337442. [PMID: 38818523 PMCID: PMC11137309 DOI: 10.3389/fphys.2024.1337442] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2023] [Accepted: 04/29/2024] [Indexed: 06/01/2024] Open
Abstract
Neurodegenerative diseases are debilitating nervous system disorders attributed to various conditions such as body aging, gene mutations, genetic factors, and immune system disorders. Prominent neurodegenerative diseases include Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and multiple sclerosis. Insulin resistance refers to the inability of the peripheral and central tissues of the body to respond to insulin and effectively regulate blood sugar levels. Insulin resistance has been observed in various neurodegenerative diseases and has been suggested to induce the occurrence, development, and exacerbation of neurodegenerative diseases. Furthermore, an increasing number of studies have suggested that reversing insulin resistance may be a critical intervention for the treatment of neurodegenerative diseases. Among the numerous measures available to improve insulin sensitivity, exercise is a widely accepted strategy due to its convenience, affordability, and significant impact on increasing insulin sensitivity. This review examines the association between neurodegenerative diseases and insulin resistance and highlights the molecular mechanisms by which exercise can reverse insulin resistance under these conditions. The focus was on regulating insulin resistance through exercise and providing practical ideas and suggestions for future research focused on exercise-induced insulin sensitivity in the context of neurodegenerative diseases.
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Affiliation(s)
- Jiawen Shen
- Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Taizhou, China
| | - Xianping Wang
- School of Medicine, Taizhou University, Taizhou, China
| | - Minghui Wang
- College of Sports Medicine, Wuhan Sports University, Wuhan, China
| | - Hu Zhang
- College of Sports Medicine, Wuhan Sports University, Wuhan, China
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14
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Lewitt MS, Boyd GW. Role of the Insulin-like Growth Factor System in Neurodegenerative Disease. Int J Mol Sci 2024; 25:4512. [PMID: 38674097 PMCID: PMC11049992 DOI: 10.3390/ijms25084512] [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: 03/27/2024] [Revised: 04/16/2024] [Accepted: 04/18/2024] [Indexed: 04/28/2024] Open
Abstract
The insulin-like growth factor (IGF) system has paracrine and endocrine roles in the central nervous system. There is evidence that IGF signalling pathways have roles in the pathophysiology of neurodegenerative disease. This review focusses on Alzheimer's disease and Parkinson's disease, the two most common neurodegenerative disorders that are increasing in prevalence globally in relation to the aging population and the increasing prevalence of obesity and type 2 diabetes. Rodent models used in the study of the molecular pathways involved in neurodegeneration are described. However, currently, no animal model fully replicates these diseases. Mice with triple mutations in APP, PSEN and MAPT show promise as models for the testing of novel Alzheimer's therapies. While a causal relationship is not proven, the fact that age, obesity and T2D are risk factors in both strengthens the case for the involvement of the IGF system in these disorders. The IGF system is an attractive target for new approaches to management; however, there are gaps in our understanding that first need to be addressed. These include a focus beyond IGF-I on other members of the IGF system, including IGF-II, IGF-binding proteins and the type 2 IGF receptor.
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Affiliation(s)
- Moira S. Lewitt
- School of Health and Life Sciences, University of the West of Scotland, Paisley PA1 2BE, UK
| | - Gary W. Boyd
- School of Health and Life Sciences, University of the West of Scotland, Hamilton G72 0LH, UK;
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15
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Rhea EM, Banks WA. Insulin and the blood-brain barrier. VITAMINS AND HORMONES 2024; 126:169-190. [PMID: 39029972 DOI: 10.1016/bs.vh.2024.02.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/21/2024]
Abstract
The blood-brain barrier (BBB) predominantly regulates insulin transport into and levels within the brain. The BBB is also an important site of insulin binding and mediator of insulin receptor (INSR) signaling. The insulin transporter is separate from the INSR, highlighting the important, unique role of each protein in this structure. After a brief introduction on the structure of insulin and the INSR, we discuss the importance of insulin interactions at the BBB, the properties of the insulin transporter and the role of the BBB insulin transporter in various physiological conditions. We go on to further describe insulin BBB signaling and the impact not only within brain endothelial cells but also the cascade into other cell types within the brain. We close with future considerations to advance our knowledge about the importance of insulin at the BBB.
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Affiliation(s)
- Elizabeth M Rhea
- Geriatric Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA, United States; Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington School of Medicine, Seattle, WA, United States.
| | - William A Banks
- Geriatric Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA, United States; Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington School of Medicine, Seattle, WA, United States
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16
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Banks WA. Viktor Mutt lecture: Peptides can cross the blood-brain barrier. Peptides 2023; 169:171079. [PMID: 37598757 DOI: 10.1016/j.peptides.2023.171079] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Revised: 08/16/2023] [Accepted: 08/16/2023] [Indexed: 08/22/2023]
Abstract
The field of peptides exploded in the 1970's and has continued to be a major area of discovery. Among the early discoveries was that peptides administered peripherally could affect brain functions. This led Kastin to propose that peptides could cross the blood-brain barrier (BBB). Although initially very controversial, Kastin, I, and others demonstrated not only that peptides can cross the BBB, but elucidated many fundamental characteristics of that passage. That work was in large part the basis of the 2022 Viktor Mutt Lectureship. Here, we review some of the early work with current updates on topics related to the penetration of peptides across the BBB. We briefly review mechanisms by which peripherally administered peptides can affect brain function without crossing the BBB, and then review the major mechanisms by which peptides and their analogs have been show to cross the BBB: transmembrane diffusion, saturable transport, and adsorptive transcytosis. Saturable transport systems are adaptable to physiologic changes and can be altered by disease states. In particular, the transport across the BBB of insulin and of pituitary adenylate cyclase activating polypeptide (PACAP) illustrate many of the concepts regarding peptide transport across the BBB.
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Affiliation(s)
- William A Banks
- Geriatric Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle 98108, WA, USA; Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington School of Medicine, Seattle, WA 98104, USA
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17
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Mohamed-Mohamed H, García-Morales V, Sánchez Lara EM, González-Acedo A, Pardo-Moreno T, Tovar-Gálvez MI, Melguizo-Rodríguez L, Ramos-Rodríguez JJ. Physiological Mechanisms Inherent to Diabetes Involved in the Development of Dementia: Alzheimer's Disease. Neurol Int 2023; 15:1253-1272. [PMID: 37873836 PMCID: PMC10594452 DOI: 10.3390/neurolint15040079] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2023] [Revised: 10/06/2023] [Accepted: 10/08/2023] [Indexed: 10/25/2023] Open
Abstract
Type 2 diabetes mellitus (T2D) is a metabolic disease reaching pandemic levels worldwide. In parallel, Alzheimer's disease (AD) and vascular dementia (VaD) are the two leading causes of dementia in an increasingly long-living Western society. Numerous epidemiological studies support the role of T2D as a risk factor for the development of dementia. However, few basic science studies have focused on the possible mechanisms involved in this relationship. On the other hand, this review of the literature also aims to explore the relationship between T2D, AD and VaD. The data found show that there are several alterations in the central nervous system that may be promoting the development of T2D. In addition, there are some mechanisms by which T2D may contribute to the development of neurodegenerative diseases such as AD or VaD.
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Affiliation(s)
- Himan Mohamed-Mohamed
- Department of Physiology, Faculty of Health Sciences of Ceuta, University of Granada, 51001 Ceuta, Spain
| | - Victoria García-Morales
- Physiology Area, Department of Biomedicine, Biotechnology and Public Health, Faculty of Medicine, University of Cádiz, Pl. Falla, 9, 11003 Cádiz, Spain
| | - Encarnación María Sánchez Lara
- Department of Personalidad, Evaluación y Tratamiento Psicológico, Faculty of Health Sciences (Ceuta), University of Granada, 51001 Ceuta, Spain;
| | - Anabel González-Acedo
- Department of Nursing, Faculty of Health Sciences of Ceuta, University of Granada, 51001 Ceuta, Spain
- Biomedical Group (BIO277), Department of Nursing, Faculty of Health Sciences, University of Granada, 18016 Granada, Spain
| | - Teresa Pardo-Moreno
- Department of Nursing, Faculty of Health Sciences of Ceuta, University of Granada, 51001 Ceuta, Spain
| | - María Isabel Tovar-Gálvez
- Department of Nursing, Faculty of Health Sciences of Ceuta, University of Granada, 51001 Ceuta, Spain
| | - Lucía Melguizo-Rodríguez
- Department of Nursing, Faculty of Health Sciences of Ceuta, University of Granada, 51001 Ceuta, Spain
- Biomedical Group (BIO277), Department of Nursing, Faculty of Health Sciences, University of Granada, 18016 Granada, Spain
| | - Juan José Ramos-Rodríguez
- Department of Physiology, Faculty of Health Sciences of Ceuta, University of Granada, 51001 Ceuta, Spain
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18
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Alves SS, Servilha-Menezes G, Rossi L, da Silva Junior RMP, Garcia-Cairasco N. Evidence of disturbed insulin signaling in animal models of Alzheimer's disease. Neurosci Biobehav Rev 2023; 152:105326. [PMID: 37479008 DOI: 10.1016/j.neubiorev.2023.105326] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2022] [Revised: 06/02/2023] [Accepted: 07/17/2023] [Indexed: 07/23/2023]
Abstract
Since glucose reuptake by neurons is mostly independent of insulin, it has been an intriguing question whether insulin has or not any roles in the brain. Consequently, the identification of insulin receptors in the central nervous system has fueled investigations of insulin functions in the brain. It is also already known that insulin can influence glucose reuptake by neurons, mostly during activities that have the highest energy demand. The identification of high density of insulin receptors in the hippocampus also suggests that insulin may present important roles related to memory. In this context, studies have reported worse performance in cognitive tests among diabetic patients. In addition, alterations in the regulation of central insulin pathways have been observed in the brains of Alzheimer's disease (AD) patients. In fact, some authors have proposed AD as a third type of diabetes and recently, our group proposed insulin resistance as a common link between different AD hypotheses. Therefore, in the present narrative review, we intend to revise and gather the evidence of disturbed insulin signaling in experimental animal models of AD.
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Affiliation(s)
- Suélen Santos Alves
- Department of Neurosciences and Behavioral Sciences, Ribeirão Preto Medical School, University of São Paulo (FMRP-USP), Brazil
| | - Gabriel Servilha-Menezes
- Department of Physiology, Ribeirão Preto Medical School - University of São Paulo (FMRP-USP), Brazil
| | - Leticia Rossi
- Department of Physiology, Ribeirão Preto Medical School - University of São Paulo (FMRP-USP), Brazil
| | - Rui Milton Patrício da Silva Junior
- Department of Physiology, Ribeirão Preto Medical School - University of São Paulo (FMRP-USP), Brazil; Institute of Neuroscience of Castilla y León, University of Salamanca, Salamanca, Spain
| | - Norberto Garcia-Cairasco
- Department of Neurosciences and Behavioral Sciences, Ribeirão Preto Medical School, University of São Paulo (FMRP-USP), Brazil; Department of Physiology, Ribeirão Preto Medical School - University of São Paulo (FMRP-USP), Brazil.
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19
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Wątroba M, Grabowska AD, Szukiewicz D. Effects of Diabetes Mellitus-Related Dysglycemia on the Functions of Blood-Brain Barrier and the Risk of Dementia. Int J Mol Sci 2023; 24:10069. [PMID: 37373216 DOI: 10.3390/ijms241210069] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2023] [Revised: 06/11/2023] [Accepted: 06/12/2023] [Indexed: 06/29/2023] Open
Abstract
Diabetes mellitus is one of the most common metabolic diseases worldwide, and its long-term complications include neuropathy, referring both to the peripheral and to the central nervous system. Detrimental effects of dysglycemia, especially hyperglycemia, on the structure and function of the blood-brain barrier (BBB), seem to be a significant backgrounds of diabetic neuropathy pertaining to the central nervous system (CNS). Effects of hyperglycemia, including excessive glucose influx to insulin-independent cells, may induce oxidative stress and secondary innate immunity dependent inflammatory response, which can damage cells within the CNS, thus promoting neurodegeneration and dementia. Advanced glycation end products (AGE) may exert similar, pro-inflammatory effects through activating receptors for advanced glycation end products (RAGE), as well as some pattern-recognition receptors (PRR). Moreover, long-term hyperglycemia can promote brain insulin resistance, which may in turn promote Aβ aggregate accumulation and tau hyperphosphorylation. This review is focused on a detailed analysis of the effects mentioned above towards the CNS, with special regard to mechanisms taking part in the pathogenesis of central long-term complications of diabetes mellitus initiated by the loss of BBB integrity.
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Affiliation(s)
- Mateusz Wątroba
- Laboratory of the Blood-Brain Barrier, Department of Biophysics, Physiology & Pathophysiology, Medical University of Warsaw, Chałubinskiego 5, 02-004 Warsaw, Poland
| | - Anna D Grabowska
- Laboratory of the Blood-Brain Barrier, Department of Biophysics, Physiology & Pathophysiology, Medical University of Warsaw, Chałubinskiego 5, 02-004 Warsaw, Poland
| | - Dariusz Szukiewicz
- Laboratory of the Blood-Brain Barrier, Department of Biophysics, Physiology & Pathophysiology, Medical University of Warsaw, Chałubinskiego 5, 02-004 Warsaw, Poland
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20
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Nguyen V, Thomas P, Pemberton S, Babin A, Noonan C, Weaver R, Banks WA, Rhea EM. Central nervous system insulin signaling can influence the rate of insulin influx into brain. Fluids Barriers CNS 2023; 20:28. [PMID: 37076875 PMCID: PMC10114367 DOI: 10.1186/s12987-023-00431-6] [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: 12/09/2022] [Accepted: 04/10/2023] [Indexed: 04/21/2023] Open
Abstract
BACKGROUND Insulin transport across the blood-brain barrier (BBB) is a highly regulated, saturable process, known to be affected by many peripheral substrates including insulin itself and triglycerides. This is in contrast to insulin leakage into peripheral tissues. Whether the central nervous system (CNS) can control the rate of insulin uptake by brain remains to be determined. Insulin BBB interactions are impaired in Alzheimer's disease (AD) and CNS insulin resistance is widely prevalent in AD. Therefore, if CNS insulin controls the rate of insulin transport across the BBB, then the defective transport of insulin seen in AD could be one manifestation of the resistance to CNS insulin observed in AD. METHODS We investigated whether enhancing CNS insulin levels or induction of CNS insulin resistance using an inhibitor of the insulin receptor altered the blood-to-brain transport of radioactively labeled insulin in young, healthy mice. RESULTS We found that insulin injected directly into the brain decreased insulin transport across the BBB for whole brain and the olfactory bulb in male mice, whereas insulin receptor blockade decreased transport in female mice for whole brain and hypothalamus. Intranasal insulin, currently being investigated as a treatment in AD patients, decreased transport across the BBB of the hypothalamus. CONCLUSIONS These results suggest CNS insulin can control the rate of insulin brain uptake, connecting CNS insulin resistance to the rate of insulin transport across the BBB.
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Affiliation(s)
- Van Nguyen
- School of Medicine, University of Washington, Seattle, WA, 98195, USA
| | - Peter Thomas
- Geriatric Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA, 98108, USA
| | - Sarah Pemberton
- Geriatric Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA, 98108, USA
- University of Washington, Seattle, WA, 98195, USA
| | - Alice Babin
- Geriatric Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA, 98108, USA
| | - Cassidy Noonan
- Geriatric Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA, 98108, USA
- University of Washington, Seattle, WA, 98195, USA
| | - Riley Weaver
- Geriatric Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA, 98108, USA
| | - William A Banks
- Geriatric Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA, 98108, USA
- Department of Medicine, Division of Gerontology and Geriatric Medicine, University of Washington, Seattle, WA, 98195, USA
| | - Elizabeth M Rhea
- Geriatric Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA, 98108, USA.
- Department of Medicine, Division of Gerontology and Geriatric Medicine, University of Washington, Seattle, WA, 98195, USA.
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21
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Gruber J, Hanssen R, Qubad M, Bouzouina A, Schack V, Sochor H, Schiweck C, Aichholzer M, Matura S, Slattery DA, Zopf Y, Borgland SL, Reif A, Thanarajah SE. Impact of insulin and insulin resistance on brain dopamine signalling and reward processing- an underexplored mechanism in the pathophysiology of depression? Neurosci Biobehav Rev 2023; 149:105179. [PMID: 37059404 DOI: 10.1016/j.neubiorev.2023.105179] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Revised: 04/04/2023] [Accepted: 04/11/2023] [Indexed: 04/16/2023]
Abstract
Type 2 diabetes and major depressive disorder (MDD) are the leading causes of disability worldwide and have a high comorbidity rate with fatal outcomes. Despite the long-established association between these conditions, the underlying molecular mechanisms remain unknown. Since the discovery of insulin receptors in the brain and the brain's reward system, evidence has accumulated indicating that insulin modulates dopaminergic (DA) signalling and reward behaviour. Here, we review the evidence from rodent and human studies, that insulin resistance directly alters central DA pathways, which may result in motivational deficits and depressive symptoms. Specifically, we first elaborate on the differential effects of insulin on DA signalling in the ventral tegmental area (VTA) - the primary DA source region in the midbrain - and the striatum as well as its effects on behaviour. We then focus on the alterations induced by insulin deficiency and resistance. Finally, we review the impact of insulin resistance in DA pathways in promoting depressive symptoms and anhedonia on a molecular and epidemiological level and discuss its relevance for stratified treatment strategies.
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Affiliation(s)
- Judith Gruber
- Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, Frankfurt, Germany
| | - Ruth Hanssen
- University of Cologne, Faculty of Medicine and University Hospital Cologne, Policlinic for Endocrinology, Diabetology and Prevention Medicine, Germany
| | - Mishal Qubad
- Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, Frankfurt, Germany
| | - Aicha Bouzouina
- Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, Frankfurt, Germany
| | - Vivi Schack
- Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, Frankfurt, Germany
| | - Hannah Sochor
- Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, Frankfurt, Germany
| | - Carmen Schiweck
- Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, Frankfurt, Germany
| | - Mareike Aichholzer
- Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, Frankfurt, Germany
| | - Silke Matura
- Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, Frankfurt, Germany
| | - David A Slattery
- Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, Frankfurt, Germany
| | - Yurdaguel Zopf
- Hector-Center for Nutrition, Exercise and Sports, Department of Medicine 1, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, 91054 Erlangen, Germany
| | - Stephanie L Borgland
- Department of Physiology and Pharmacology, Hotchkiss Brain Institute, The University of Calgary, Calgary, Canada
| | - Andreas Reif
- Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, Frankfurt, Germany
| | - Sharmili Edwin Thanarajah
- Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, Frankfurt, Germany.
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22
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A Review on Phyto-Therapeutic Approaches in Alzheimer's Disease. J Funct Biomater 2023; 14:jfb14010050. [PMID: 36662097 PMCID: PMC9861153 DOI: 10.3390/jfb14010050] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Revised: 12/29/2022] [Accepted: 01/14/2023] [Indexed: 01/19/2023] Open
Abstract
Neurodegenerative diseases occur due to progressive and sometimes irreversible loss of function and death of nerve cells. A great deal of effort is being made to understand the pathogenesis of neurodegenerative diseases. In particular, the prevalence of Alzheimer's disease (AD) is quite high, and only symptomatic therapy is available due to the absence of radical treatment. The aim of this review is to try to elucidate the general pathogenesis of AD, to provide information about the limit points of symptomatic treatment approaches, and to emphasize the potential neurologic effects of phytocompounds as new tools as therapeutic agents for disease prevention, retardation, and therapy. This survey also covers the notable properties of herbal compounds such as their effects on the inhibition of an enzyme called acetylcholinesterase, which has significant value in the treatment of AD. It has been proven that phytopharmaceuticals have long-term effects that could protect nervous system health, eliminate inflammatory responses, improve cognitive damage, provide anti-aging effects in the natural aging process, and alleviate dementia sequelae. Herbal-based therapeutic agents can afford many advantages and can be used as potentially as new-generation therapeutics or complementary agents with high compliance, fewer adverse effects, and lower cost in comparison to the traditional pharmaceutical agents in the fight against AD.
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23
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Ferris HA. Insulin and neurodegenerative diseases. INSULIN 2023:315-338. [DOI: 10.1016/b978-0-323-91707-0.00012-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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24
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Banks WA, Noonan C, Rhea EM. Evidence for an alternative insulin transporter at the blood-brain barrier. AGING PATHOBIOLOGY AND THERAPEUTICS 2022; 4:100-108. [PMID: 36644126 PMCID: PMC9837797 DOI: 10.31491/apt.2022.12.100] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Accumulating evidence suggests there is an alternative insulin transporter besides the insulin receptor at the blood-brain barrier (BBB), responsible for shuttling insulin from the circulation into the brain. In this review, we summarize key features of the BBB and what makes it unique compared to other capillary beds; summarize what we know about insulin BBB transport; provide an extensive list of diseases, physiological states, and serum factors tested in modifying insulin BBB transport; and lastly, highlight potential alternative transport systems that may be involved in or have already been tested in mediating insulin BBB transport. Identifying the transport system for insulin at the BBB would aide in controlling central nervous system (CNS) insulin levels in multiple diseases and conditions including Alzheimer's disease (AD) and obesity, where availability of insulin to the CNS is limited.
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Affiliation(s)
- William A. Banks
- Department of Medicine, Division of Gerontology and Geriatric Medicine, University of Washington, Seattle, WA 98195, USA
- Geriatric Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108, USA
| | - Cassidy Noonan
- Research and Development, Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108, USA
- University of Washington, Seattle, WA 98195, USA
| | - Elizabeth M. Rhea
- Department of Medicine, Division of Gerontology and Geriatric Medicine, University of Washington, Seattle, WA 98195, USA
- Geriatric Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108, USA
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25
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Pemberton S, Galindo DC, Schwartz MW, Banks WA, Rhea EM. Endocytosis of insulin at the blood-brain barrier. FRONTIERS IN DRUG DELIVERY 2022; 2:1062366. [PMID: 37936681 PMCID: PMC10629879 DOI: 10.3389/fddev.2022.1062366] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/09/2023]
Abstract
For insulin to act within the brain, it is primarily transported from the blood across the blood-brain barrier (BBB). However, the endocytic machinery necessary for delivering insulin to the brain remains unknown. Additionally, there are processes within the brain endothelial cell that are designed to respond to insulin binding and elicit intracellular signaling. Using pharmacological inhibitors of different types of endocytosis (clathrin-vs. caveolin-mediated), we investigated molecular mediators of both insulin BBB binding in isolated mouse brain microvessels and BBB insulin transport in mice studied by brain perfusion. We found clathrin-mediated mechanisms responsible for insulin surface binding in isolated brain microvessels while caveolin-mediated endocytosis may mediate BBB insulin transport specifically in the hypothalamus. These results further define the molecular machinery necessary for transporting insulin into the CNS and highlight the distinction between insulin internalization for transendothelial transport vs. intracellular signaling.
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Affiliation(s)
- Sarah Pemberton
- Geriatric Research Education and Clinical Center, VA Puget Sound Health Care System, Seattle, WA, United States
| | - Demi C Galindo
- Geriatric Research Education and Clinical Center, VA Puget Sound Health Care System, Seattle, WA, United States
| | - Michael W Schwartz
- Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, School of Medicine, University of Washington, Seattle, WA, United States
| | - William A Banks
- Geriatric Research Education and Clinical Center, VA Puget Sound Health Care System, Seattle, WA, United States
- Division of Gerontology and Geriatric Medicine, Department of Medicine, School of Medicine, University of Washington, Seattle, WA, United States
| | - Elizabeth M Rhea
- Geriatric Research Education and Clinical Center, VA Puget Sound Health Care System, Seattle, WA, United States
- Division of Gerontology and Geriatric Medicine, Department of Medicine, School of Medicine, University of Washington, Seattle, WA, United States
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26
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Bakker W, Imbernon M, Salinas CG, Moro Chao DH, Hassouna R, Morel C, Martin C, Leger C, Denis RG, Castel J, Peter A, Heni M, Maetzler W, Nielsen HS, Duquenne M, Schwaninger M, Lundh S, Johan Hogendorf WF, Gangarossa G, Secher A, Hecksher-Sørensen J, Pedersen TÅ, Prevot V, Luquet S. Acute changes in systemic glycemia gate access and action of GLP-1R agonist on brain structures controlling energy homeostasis. Cell Rep 2022; 41:111698. [PMID: 36417883 PMCID: PMC9715912 DOI: 10.1016/j.celrep.2022.111698] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Revised: 08/19/2022] [Accepted: 10/20/2022] [Indexed: 11/23/2022] Open
Abstract
Therapies based on glucagon-like peptide-1 (GLP-1) long-acting analogs and insulin are often used in the treatment of metabolic diseases. Both insulin and GLP-1 receptors are expressed in metabolically relevant brain regions, suggesting a cooperative action. However, the mechanisms underlying the synergistic actions of insulin and GLP-1R agonists remain elusive. In this study, we show that insulin-induced hypoglycemia enhances GLP-1R agonists entry in hypothalamic and area, leading to enhanced whole-body fat oxidation. Mechanistically, this phenomenon relies on the release of tanycyctic vascular endothelial growth factor A, which is selectively impaired after calorie-rich diet exposure. In humans, low blood glucose also correlates with enhanced blood-to-brain passage of insulin, suggesting that blood glucose gates the passage other energy-related signals in the brain. This study implies that the preventing hyperglycemia is important to harnessing the full benefit of GLP-1R agonist entry in the brain and action onto lipid mobilization and body weight loss.
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Affiliation(s)
- Wineke Bakker
- Université Paris Cité, CNRS, Unité de Biologie Fonctionnelle et Adaptative, 75013 Paris, France,Global Drug Discovery, Novo Nordisk A/S, Måløv, Denmark,Corresponding author
| | - Monica Imbernon
- University Lille, Inserm, CHU Lille, Laboratory of Development and Plasticity of the Neuroendocrine Brain, Lille Neuroscience & Cognition, EGID, UMR-S 1172, 59000 Lille, France
| | - Casper Gravesen Salinas
- Global Drug Discovery, Novo Nordisk A/S, Måløv, Denmark,Image Analysis & Computer Graphics, Department of Applied Mathematics and Computer Science, Technical University of Denmark, Kgs. Lyngby, Denmark,Gubra ApS, Hørsholm Kongevej 11B, 2970 Hørsholm, Denmark
| | | | - Rim Hassouna
- Université Paris Cité, CNRS, Unité de Biologie Fonctionnelle et Adaptative, 75013 Paris, France
| | - Chloe Morel
- Université Paris Cité, CNRS, Unité de Biologie Fonctionnelle et Adaptative, 75013 Paris, France
| | - Claire Martin
- Université Paris Cité, CNRS, Unité de Biologie Fonctionnelle et Adaptative, 75013 Paris, France
| | - Caroline Leger
- Université Paris Cité, CNRS, Unité de Biologie Fonctionnelle et Adaptative, 75013 Paris, France
| | - Raphael G.P. Denis
- Université Paris Cité, CNRS, Unité de Biologie Fonctionnelle et Adaptative, 75013 Paris, France,Institut Cochin, Université Paris Cité, INSERM U1016, CNRS UMR 8104, 75014 Paris, France
| | - Julien Castel
- Université Paris Cité, CNRS, Unité de Biologie Fonctionnelle et Adaptative, 75013 Paris, France
| | - Andreas Peter
- Institute of Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany,German Center for Diabetes Research (DZD), Tübingen, Germany,Institute for Clinical Chemistry and Pathobiochemistry, Department for Diagnostic Laboratory Medicine, University Hospital of Tübingen, Tübingen, Germany
| | - Martin Heni
- Department of Internal Medicine IV, Division of Endocrinology, Diabetology and Nephrology, University of Tübingen, Tübingen, Germany,Institute of Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany,German Center for Diabetes Research (DZD), Tübingen, Germany
| | - Walter Maetzler
- Department of Neurodegenerative Diseases, Center of Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany,German Center for Neurodegenerative Diseases, Tübingen, Germany,Department of Neurology, University of Kiel, Kiel, Germany
| | | | - Manon Duquenne
- University Lille, Inserm, CHU Lille, Laboratory of Development and Plasticity of the Neuroendocrine Brain, Lille Neuroscience & Cognition, EGID, UMR-S 1172, 59000 Lille, France
| | - Markus Schwaninger
- Institute for Experimental and Clinical Pharmacology and Toxicology, University of Lübeck, Lübeck, Germany
| | - Sofia Lundh
- Global Drug Discovery, Novo Nordisk A/S, Måløv, Denmark
| | | | - Giuseppe Gangarossa
- Université Paris Cité, CNRS, Unité de Biologie Fonctionnelle et Adaptative, 75013 Paris, France
| | - Anna Secher
- Global Drug Discovery, Novo Nordisk A/S, Måløv, Denmark
| | - Jacob Hecksher-Sørensen
- Global Drug Discovery, Novo Nordisk A/S, Måløv, Denmark,Gubra ApS, Hørsholm Kongevej 11B, 2970 Hørsholm, Denmark
| | | | - Vincent Prevot
- University Lille, Inserm, CHU Lille, Laboratory of Development and Plasticity of the Neuroendocrine Brain, Lille Neuroscience & Cognition, EGID, UMR-S 1172, 59000 Lille, France
| | - Serge Luquet
- Université Paris Cité, CNRS, Unité de Biologie Fonctionnelle et Adaptative, 75013 Paris, France,Corresponding author
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27
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Olszewski PK, Noble EE, Paiva L, Ueta Y, Blevins JE. Oxytocin as a potential pharmacological tool to combat obesity. J Neuroendocrinol 2022; 34:e13106. [PMID: 35192207 PMCID: PMC9372234 DOI: 10.1111/jne.13106] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Revised: 02/06/2022] [Accepted: 02/08/2022] [Indexed: 11/30/2022]
Abstract
The neuropeptide oxytocin (OT) has emerged as an important anorexigen in the regulation of food intake and energy balance. It has been shown that the release of OT and activation of hypothalamic OT neurons coincide with food ingestion. Its effects on feeding have largely been attributed to limiting meal size through interactions in key regulatory brain regions governing the homeostatic control of food intake such as the hypothalamus and hindbrain in addition to key feeding reward areas such as the nucleus accumbens and ventral tegmental area. Furthermore, the magnitude of an anorexigenic response to OT and feeding-related activation of the brain OT circuit are modified by the composition and flavor of a diet, as well as by a social context in which a meal is consumed. OT is particularly effective in reducing consumption of carbohydrates and sweet tastants. Pharmacologic, genetic, and pair-feeding studies indicate that OT-elicited weight loss cannot be fully explained by reductions of food intake and that the overall impact of OT on energy balance is also partly a result of OT-elicited changes in lipolysis, energy expenditure, and glucose regulation. Peripheral administration of OT mimics many of its effects when it is given into the central nervous system, raising the questions of whether and to what extent circulating OT acts through peripheral OT receptors to regulate energy balance. Although OT has been found to elicit weight loss in female mice, recent studies have indicated that sex and estrous cycle may impact oxytocinergic modulation of food intake. Despite the overall promising basic research data, attempts to use OT in the clinical setting to combat obesity and overeating have generated somewhat mixed results. The focus of this mini-review is to briefly summarize the role of OT in feeding and metabolism, address gaps and inconsistencies in our knowledge, and discuss some of the limitations to the potential use of chronic OT that should help guide future research on OT as a tailor-made anti-obesity therapeutic.
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Affiliation(s)
- Pawel K Olszewski
- Faculty of Science and Engineering, University of Waikato, Waikato, New Zealand
- Department of Food Science and Nutrition, College of Food, Agricultural and Natural Resource Sciences, University of Minnesota, St Paul, Minnesota, USA
- Department of Integrative Biology and Physiology, Medical School, University of Minnesota, Minneapolis, Minnesota, USA
| | - Emily E Noble
- Department of Nutritional Sciences, University of Georgia, Athens, Georgia, USA
| | - Luis Paiva
- Instituto de Ciencia Animal, Facultad de Ciencias Veterinarias, Universidad Austral de Chile, Valdivia, Chile
| | - Yoichi Ueta
- Department of Physiology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Fukuoka, Japan
| | - James E Blevins
- Department of Veterans Affairs Medical Center, VA Puget Sound Health Care System, Office of Research and Development Medical Research Service, Seattle, Washington, USA
- Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, University of Washington School of Medicine, Seattle, Washington, USA
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28
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Falling Short: The Contribution of Central Insulin Receptors to Gait Dysregulation in Brain Aging. Biomedicines 2022; 10:biomedicines10081923. [PMID: 36009470 PMCID: PMC9405648 DOI: 10.3390/biomedicines10081923] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Revised: 07/27/2022] [Accepted: 07/29/2022] [Indexed: 11/23/2022] Open
Abstract
Insulin resistance, which manifests as a reduction of insulin receptor signaling, is known to correlate with pathological changes in peripheral tissues as well as in the brain. Central insulin resistance has been associated with impaired cognitive performance, decreased neuronal health, and reduced brain metabolism; however, the mechanisms underlying central insulin resistance and its impact on brain regions outside of those associated with cognition remain unclear. Falls are a leading cause of both fatal and non-fatal injuries in the older population. Despite this, there is a paucity of work focused on age-dependent alterations in brain regions associated with ambulatory control or potential therapeutic approaches to target these processes. Here, we discuss age-dependent alterations in central modalities that may contribute to gait dysregulation, summarize current data supporting the role of insulin signaling in the brain, and highlight key findings that suggest insulin receptor sensitivity may be preserved in the aged brain. Finally, we present novel results showing that administration of insulin to the somatosensory cortex of aged animals can alter neuronal communication, cerebral blood flow, and the motivation to ambulate, emphasizing the need for further investigations of intranasal insulin as a clinical management strategy in the older population.
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29
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Stewart J, Arneson A, Byrd M, Negron-Perez V, Newberne H, White R, El-Kadi S, Ealy A, Rhoads R, Rhoads M. Comparison of production-related responses to hyperinsulinemia and hypoglycemia induced by clamp procedures or heat stress of lactating dairy cattle. J Dairy Sci 2022; 105:8439-8453. [DOI: 10.3168/jds.2022-21922] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2022] [Accepted: 05/12/2022] [Indexed: 11/19/2022]
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Abstract
Mice with insulin receptor (IR)-deficient astrocytes (GFAP-IR knockout [KO] mice) show blunted responses to insulin and reduced brain glucose uptake, whereas IR-deficient astrocytes show disturbed mitochondrial responses to glucose. While exploring the functional impact of disturbed mitochondrial function in astrocytes, we observed that GFAP-IR KO mice show uncoupling of brain blood flow with glucose uptake. Since IR-deficient astrocytes show higher levels of reactive oxidant species (ROS), this leads to stimulation of hypoxia-inducible factor-1α and, consequently, of the vascular endothelial growth factor angiogenic pathway. Indeed, GFAP-IR KO mice show disturbed brain vascularity and blood flow that is normalized by treatment with the antioxidant N-acetylcysteine (NAC). NAC ameliorated high ROS levels, normalized angiogenic signaling and mitochondrial function in IR-deficient astrocytes, and normalized neurovascular coupling in GFAP-IR KO mice. Our results indicate that by modulating glucose uptake and angiogenesis, insulin receptors in astrocytes participate in neurovascular coupling.
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31
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Li M, Chi X, Wang Y, Setrerrahmane S, Xie W, Xu H. Trends in insulin resistance: insights into mechanisms and therapeutic strategy. Signal Transduct Target Ther 2022; 7:216. [PMID: 35794109 PMCID: PMC9259665 DOI: 10.1038/s41392-022-01073-0] [Citation(s) in RCA: 307] [Impact Index Per Article: 102.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Revised: 06/15/2022] [Accepted: 06/20/2022] [Indexed: 02/06/2023] Open
Abstract
The centenary of insulin discovery represents an important opportunity to transform diabetes from a fatal diagnosis into a medically manageable chronic condition. Insulin is a key peptide hormone and mediates the systemic glucose metabolism in different tissues. Insulin resistance (IR) is a disordered biological response for insulin stimulation through the disruption of different molecular pathways in target tissues. Acquired conditions and genetic factors have been implicated in IR. Recent genetic and biochemical studies suggest that the dysregulated metabolic mediators released by adipose tissue including adipokines, cytokines, chemokines, excess lipids and toxic lipid metabolites promote IR in other tissues. IR is associated with several groups of abnormal syndromes that include obesity, diabetes, metabolic dysfunction-associated fatty liver disease (MAFLD), cardiovascular disease, polycystic ovary syndrome (PCOS), and other abnormalities. Although no medication is specifically approved to treat IR, we summarized the lifestyle changes and pharmacological medications that have been used as efficient intervention to improve insulin sensitivity. Ultimately, the systematic discussion of complex mechanism will help to identify potential new targets and treat the closely associated metabolic syndrome of IR.
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Affiliation(s)
- Mengwei Li
- The Engineering Research Center of Synthetic Peptide Drug Discovery and Evaluation of Jiangsu Province, China Pharmaceutical University, Nanjing, 210009, China
- State Key Laboratory of Natural Medicines, Ministry of Education, China Pharmaceutical University, Nanjing, 210009, China
| | - Xiaowei Chi
- Development Center for Medical Science & Technology National Health Commission of the People's Republic of China, 100044, Beijing, China
| | - Ying Wang
- The Engineering Research Center of Synthetic Peptide Drug Discovery and Evaluation of Jiangsu Province, China Pharmaceutical University, Nanjing, 210009, China
- State Key Laboratory of Natural Medicines, Ministry of Education, China Pharmaceutical University, Nanjing, 210009, China
| | | | - Wenwei Xie
- The Engineering Research Center of Synthetic Peptide Drug Discovery and Evaluation of Jiangsu Province, China Pharmaceutical University, Nanjing, 210009, China
- State Key Laboratory of Natural Medicines, Ministry of Education, China Pharmaceutical University, Nanjing, 210009, China
| | - Hanmei Xu
- The Engineering Research Center of Synthetic Peptide Drug Discovery and Evaluation of Jiangsu Province, China Pharmaceutical University, Nanjing, 210009, China.
- State Key Laboratory of Natural Medicines, Ministry of Education, China Pharmaceutical University, Nanjing, 210009, China.
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32
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Rhea EM, Banks WA, Raber J. Insulin Resistance in Peripheral Tissues and the Brain: A Tale of Two Sites. Biomedicines 2022; 10:1582. [PMID: 35884888 PMCID: PMC9312939 DOI: 10.3390/biomedicines10071582] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Revised: 06/27/2022] [Accepted: 06/29/2022] [Indexed: 12/12/2022] Open
Abstract
The concept of insulin resistance has been around since a few decades after the discovery of insulin itself. To allude to the classic Charles Dicken's novel published 62 years before the discovery of insulin, in some ways, this is the best of times, as the concept of insulin resistance has expanded to include the brain, with the realization that insulin has a life beyond the regulation of glucose. In other ways, it is the worst of times as insulin resistance is implicated in devastating diseases, including diabetes mellitus, obesity, and Alzheimer's disease (AD) that affect the brain. Peripheral insulin resistance affects nearly a quarter of the United States population in adults over age 20. More recently, it has been implicated in AD, with the degree of brain insulin resistance correlating with cognitive decline. This has led to the investigation of brain or central nervous system (CNS) insulin resistance and the question of the relation between CNS and peripheral insulin resistance. While both may involve dysregulated insulin signaling, the two conditions are not identical and not always interlinked. In this review, we compare and contrast the similarities and differences between peripheral and CNS insulin resistance. We also discuss how an apolipoprotein involved in insulin signaling and related to AD, apolipoprotein E (apoE), has distinct pools in the periphery and CNS and can indirectly affect each system. As these systems are both separated but also linked via the blood-brain barrier (BBB), we discuss the role of the BBB in mediating some of the connections between insulin resistance in the brain and in the peripheral tissues.
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Affiliation(s)
- Elizabeth M. Rhea
- Department of Medicine, Division of Gerontology and Geriatric Medicine, University of Washington, Seattle, WA 98195, USA; (E.M.R.); (W.A.B.)
- Geriatric Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108, USA
| | - William A. Banks
- Department of Medicine, Division of Gerontology and Geriatric Medicine, University of Washington, Seattle, WA 98195, USA; (E.M.R.); (W.A.B.)
- Geriatric Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108, USA
| | - Jacob Raber
- Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR 97239, USA
- Departments of Neurology and Radiation Medicine, Division of Neuroscience, ONPRC, Oregon Health & Science University, Portland, OR 97239, USA
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33
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McMillan NJ, Soares RN, Harper JL, Shariffi B, Moreno-Cabañas A, Curry TB, Manrique-Acevedo C, Padilla J, Limberg JK. Role of the arterial baroreflex in the sympathetic response to hyperinsulinemia in adult humans. Am J Physiol Endocrinol Metab 2022; 322:E355-E365. [PMID: 35187960 PMCID: PMC8993537 DOI: 10.1152/ajpendo.00391.2021] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Revised: 01/28/2022] [Accepted: 02/14/2022] [Indexed: 11/22/2022]
Abstract
Muscle sympathetic nerve activity (MSNA) increases during hyperinsulinemia, primarily attributed to central nervous system effects. Whether peripheral vasodilation induced by insulin further contributes to increased MSNA via arterial baroreflex-mediated mechanisms requires further investigation. Accordingly, we examined baroreflex modulation of the MSNA response to hyperinsulinemia. We hypothesized that rescuing peripheral resistance with coinfusion of the vasoconstrictor phenylephrine would attenuate the MSNA response to hyperinsulinemia. We further hypothesized that the insulin-mediated increase in MSNA would be recapitulated with another vasodilator (sodium nitroprusside, SNP). In 33 young healthy adults (28 M/5F), MSNA (microneurography) and arterial blood pressure (BP, Finometer/brachial catheter) were measured, and total peripheral resistance (TPR, ModelFlow) and baroreflex sensitivity were calculated at rest and during intravenous infusion of insulin (n = 20) or SNP (n = 13). A subset of participants receiving insulin (n = 7) was coinfused with phenylephrine. Insulin infusion decreased TPR (P = 0.01) and increased MSNA (P < 0.01), with no effect on arterial baroreflex sensitivity or BP (P > 0.05). Coinfusion with phenylephrine returned TPR and MSNA to baseline, with no effect on arterial baroreflex sensitivity (P > 0.05). Similar to insulin, SNP decreased TPR (P < 0.02) and increased MSNA (P < 0.01), with no effect on arterial baroreflex sensitivity (P > 0.12). Acute hyperinsulinemia shifts the baroreflex stimulus-response curve to higher MSNA without changing sensitivity, likely due to insulin's peripheral vasodilatory effects. Results show that peripheral vasodilation induced by insulin contributes to increased MSNA during hyperinsulinemia.NEW & NOTEWORTHY We hypothesized that elevation in muscle sympathetic nervous system activity (MSNA) during hyperinsulinemia is mediated by its peripheral vasodilator effect on the arterial baroreflex. Using three separate protocols in humans, we observed increases in both MSNA and cardiac output during hyperinsulinemia, which we attributed to the baroreflex response to peripheral vasodilation induced by insulin. Results show that peripheral vasodilation induced by insulin contributes to increased MSNA during hyperinsulinemia.
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Affiliation(s)
- Neil J McMillan
- Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, Missouri
| | - Rogerio N Soares
- Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri
| | - Jennifer L Harper
- Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, Missouri
| | - Brian Shariffi
- Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, Missouri
| | - Alfonso Moreno-Cabañas
- Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, Missouri
- Exercise Physiology Lab at Toledo, University of Castilla-La Mancha, Toledo, Spain
| | - Timothy B Curry
- Department of Anesthesia and Perioperative Medicine, Mayo Clinic, Rochester, Minnesota
| | - Camila Manrique-Acevedo
- Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Missouri, Columbia, Missouri
- Research Services, Harry S. Truman Memorial Veterans Hospital, Columbia, Missouri
| | - Jaume Padilla
- Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, Missouri
- Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri
| | - Jacqueline K Limberg
- Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, Missouri
- Department of Anesthesia and Perioperative Medicine, Mayo Clinic, Rochester, Minnesota
- Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri
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34
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Athanasaki A, Melanis K, Tsantzali I, Stefanou MI, Ntymenou S, Paraskevas SG, Kalamatianos T, Boutati E, Lambadiari V, Voumvourakis KI, Stranjalis G, Giannopoulos S, Tsivgoulis G, Paraskevas GP. Type 2 Diabetes Mellitus as a Risk Factor for Alzheimer’s Disease: Review and Meta-Analysis. Biomedicines 2022; 10:biomedicines10040778. [PMID: 35453527 PMCID: PMC9029855 DOI: 10.3390/biomedicines10040778] [Citation(s) in RCA: 47] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Revised: 03/17/2022] [Accepted: 03/25/2022] [Indexed: 01/16/2023] Open
Abstract
Alzheimer’s disease is the most common type of dementia, reaching 60–80% of case totals, and is one of the major global causes of the elderly population’s decline in functionality concerning daily life activities. Epidemiological research has already indicated that, in addition to several others metabolic factors, diabetes mellitus type 2 is a risk factor of Alzheimer’s disease. Many molecular pathways have been described, and at the same time, there are clues that suggest the connection between type 2 diabetes mellitus and Alzheimer’s disease, through specific genes, autophagy, and even inflammatory pathways. A systematic review with meta-analysis was conducted, and its main goal was to reveal the multilevel connection between these diseases.
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Affiliation(s)
- Athanasia Athanasaki
- Department of Neurology, Evangelismos Hospital, 10676 Athens, Greece; (A.A.); (S.N.)
| | - Konstantinos Melanis
- 2nd Department of Neurology, School of Medicine, National and Kapodistrian University of Athens, “Attikon” University General Hospital, 12462 Athens, Greece; (K.M.); (I.T.); (M.I.S.); (S.G.P.); (K.I.V.); (S.G.); (G.T.)
| | - Ioanna Tsantzali
- 2nd Department of Neurology, School of Medicine, National and Kapodistrian University of Athens, “Attikon” University General Hospital, 12462 Athens, Greece; (K.M.); (I.T.); (M.I.S.); (S.G.P.); (K.I.V.); (S.G.); (G.T.)
| | - Maria Ioanna Stefanou
- 2nd Department of Neurology, School of Medicine, National and Kapodistrian University of Athens, “Attikon” University General Hospital, 12462 Athens, Greece; (K.M.); (I.T.); (M.I.S.); (S.G.P.); (K.I.V.); (S.G.); (G.T.)
| | - Sofia Ntymenou
- Department of Neurology, Evangelismos Hospital, 10676 Athens, Greece; (A.A.); (S.N.)
| | - Sotirios G. Paraskevas
- 2nd Department of Neurology, School of Medicine, National and Kapodistrian University of Athens, “Attikon” University General Hospital, 12462 Athens, Greece; (K.M.); (I.T.); (M.I.S.); (S.G.P.); (K.I.V.); (S.G.); (G.T.)
| | - Theodosis Kalamatianos
- 1st Department of Neurosurgery, School of Medicine, National and Kapodistrian University of Athens, Evangelismos Hospital, 10676 Athens, Greece; (T.K.); (G.S.)
| | - Eleni Boutati
- 2nd Department of Internal Medicine, School of Medicine, National and Kapodistrian University of Athens, “Attikon” University General Hospital, 12462 Athens, Greece; (E.B.); (V.L.)
| | - Vaia Lambadiari
- 2nd Department of Internal Medicine, School of Medicine, National and Kapodistrian University of Athens, “Attikon” University General Hospital, 12462 Athens, Greece; (E.B.); (V.L.)
| | - Konstantinos I. Voumvourakis
- 2nd Department of Neurology, School of Medicine, National and Kapodistrian University of Athens, “Attikon” University General Hospital, 12462 Athens, Greece; (K.M.); (I.T.); (M.I.S.); (S.G.P.); (K.I.V.); (S.G.); (G.T.)
| | - George Stranjalis
- 1st Department of Neurosurgery, School of Medicine, National and Kapodistrian University of Athens, Evangelismos Hospital, 10676 Athens, Greece; (T.K.); (G.S.)
| | - Sotirios Giannopoulos
- 2nd Department of Neurology, School of Medicine, National and Kapodistrian University of Athens, “Attikon” University General Hospital, 12462 Athens, Greece; (K.M.); (I.T.); (M.I.S.); (S.G.P.); (K.I.V.); (S.G.); (G.T.)
| | - Georgios Tsivgoulis
- 2nd Department of Neurology, School of Medicine, National and Kapodistrian University of Athens, “Attikon” University General Hospital, 12462 Athens, Greece; (K.M.); (I.T.); (M.I.S.); (S.G.P.); (K.I.V.); (S.G.); (G.T.)
| | - George P. Paraskevas
- 2nd Department of Neurology, School of Medicine, National and Kapodistrian University of Athens, “Attikon” University General Hospital, 12462 Athens, Greece; (K.M.); (I.T.); (M.I.S.); (S.G.P.); (K.I.V.); (S.G.); (G.T.)
- Correspondence: ; Tel.: +30-2105832466
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Brown C, Pemberton S, Babin A, Abdulhameed N, Noonan C, Brown MB, Banks WA, Rhea EM. Insulin blood-brain barrier transport and interactions are greater following exercise in mice. J Appl Physiol (1985) 2022; 132:824-834. [PMID: 35175106 PMCID: PMC8917914 DOI: 10.1152/japplphysiol.00866.2021] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Exercise has multiple beneficial effects including improving peripheral insulin sensitivity, improving central function such as memory, and restoring a dysregulated blood-brain barrier (BBB). Central nervous system (CNS) insulin resistance is a common feature of cognitive impairment, including Alzheimer's disease. Delivery of insulin to the brain can improve memory. Endogenous insulin must cross the BBB to directly act within the CNS and this transport system can be affected by various physiological states and serum factors. Therefore, the current study sought to investigate whether exercise could enhance insulin BBB transport as a mechanism for the underlying benefits of exercise on cognition. We investigated radioactive insulin BBB pharmacokinetics following an acute bout of exercise in young, male and female CD-1 mice. In addition, we investigated changes in serum levels of substrates that are known to affect insulin BBB transport. Finally, we measured the basal level of a downstream protein involved in insulin receptor signaling in various brain regions as well as muscle. We found insulin BBB transport in males was greater following exercise, and in males and females to both enhance the level of insulin vascular binding and alter CNS insulin receptor signaling, independent of changes in serum factors known to alter insulin BBB transport.NEW & NOTEWORTHY Central nervous system (CNS) insulin and exercise are beneficial for cognition. CNS insulin resistance is present in Alzheimer's disease. CNS insulin levels are regulated by transport across the blood-brain barrier (BBB). We show that exercise can enhance insulin BBB transport and binding of insulin to the brain's vasculature in mice. There were no changes in serum factors known to alter insulin BBB pharmacokinetics. We conclude exercise could impact cognition through regulation of insulin BBB transport.
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Affiliation(s)
- Caitlin Brown
- 1Research and Development, Veterans Affairs Puget Sound Health Care System, Seattle, Washington
| | - Sarah Pemberton
- 1Research and Development, Veterans Affairs Puget Sound Health Care System, Seattle, Washington,2Department of Biology, University of Washington, Seattle, Washington
| | - Alice Babin
- 1Research and Development, Veterans Affairs Puget Sound Health Care System, Seattle, Washington
| | - Noor Abdulhameed
- 1Research and Development, Veterans Affairs Puget Sound Health Care System, Seattle, Washington,2Department of Biology, University of Washington, Seattle, Washington
| | - Cassidy Noonan
- 1Research and Development, Veterans Affairs Puget Sound Health Care System, Seattle, Washington,2Department of Biology, University of Washington, Seattle, Washington
| | - Mary Beth Brown
- 3Division of Physical Therapy, Department of Rehabilitation Medicine, University of Washington, Seattle, Washington
| | - William A. Banks
- 4Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington, Seattle, Washington,5Geriatric Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington
| | - Elizabeth M. Rhea
- 4Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington, Seattle, Washington,5Geriatric Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington
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36
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El Idrissi A, Alonso ADC. Pathological Human Tau Induces Alterations in the Brain Insulin Signaling Cascade. Front Neurosci 2022; 16:805046. [PMID: 35264925 PMCID: PMC8899662 DOI: 10.3389/fnins.2022.805046] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Accepted: 01/17/2022] [Indexed: 11/25/2022] Open
Abstract
The process of neurodegeneration in Alzheimer's disease has been associated with a disruption of insulin signaling cascade in neurons, and to insulin resistance. T2DM correlates with Alzheimer's disease, but mechanisms of interaction are unknown. We have developed a mouse model of tau induced neurodegeneration expressing pseudo-phosphorylated tau [Pathological Human Tau (PH-Tau)] in neurons. This model (PH-Tau-Tg) recapitulated cognitive decline and neurodegeneration observed in AD. In this study we examined if expression of PH-Tau could affect neuronal excitability and insulin receptor signaling. Neuronal excitability was investigated using intracerebral recordings of extracellular field potentials from prefrontal cortex after insulin and kainic acid (KA) injection. Analysis of baseline recordings indicated an increased excitability of PH-Tau-Tg as evidenced by higher spectrum densities (PSDs) of high frequencies brain waves. Injection of insulin (1IU, s.c) led to a decrease of fast ripples PSDs, more pronounced in PH-Tau-Tg mice than controls. Subsequent injection of kainic acid (KA, 5 mg/kg, s.c) led to significant increase in firing rate, amplitude of extracellular field potentials and PSDs of high frequency brain waves in control mice only. To further investigate the role of insulin in PH-Tau-Tg mice, we subjected mice to a glucose tolerance test. We found that PH-Tau-Tg mice were significantly hyperglycemic prior to glucose injection. Interestingly, the PH-Tau-Tg mice showed a moderate increase at 30 min due to the higher baseline, indicating a low sensitivity of insulin receptor in these mice. This is consistent with increased levels of activated insulin receptors in the brain and the inhibitory effect of insulin on ictal activity post KA injection in PH-Tau-Tg mice. We suggest that these mice have reduced insulin sensitivity (hyperglycemia) and as a compensatory mechanism there is overactivation/expression of insulin receptor in the brain rendering neuronal circuits resistant to seizure induction after injection of insulin. These data indicate that insulin signal transduction pathway is altered in PH-Tau-Tg mice, and that injection of exogenous insulin reduces hypersynchronous bursting activity of field potentials recorded from cortical neuronal circuits. We propose that the appearance of abnormal tau might potentiate the toxic environment by interfering with the insulin signaling cascade in the brain of patients with Alzheimer's disease.
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Affiliation(s)
- Abdeslem El Idrissi
- Department of Biology and Center for Developmental Neuroscience, College of Staten Island, The City University of New York, New York, NY, United States,Biology Program, The Graduate Center, The City University of New York, New York, NY, United States,*Correspondence: Abdeslem El Idrissi,
| | - Alejandra del Carmen Alonso
- Department of Biology and Center for Developmental Neuroscience, College of Staten Island, The City University of New York, New York, NY, United States,Biology Program, The Graduate Center, The City University of New York, New York, NY, United States,Alejandra del Carmen Alonso,
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37
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Stranahan AM. Visceral adiposity, inflammation, and hippocampal function in obesity. Neuropharmacology 2021; 205:108920. [PMID: 34902347 DOI: 10.1016/j.neuropharm.2021.108920] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Revised: 11/09/2021] [Accepted: 12/08/2021] [Indexed: 02/06/2023]
Abstract
The 'apple-shaped' anatomical pattern that accompanies visceral adiposity increases risk for multiple chronic diseases, including conditions that impact the brain, such as diabetes and hypertension. However, distinguishing between the consequences of visceral obesity, as opposed to visceral adiposity-associated metabolic and cardiovascular pathologies, presents certain challenges. This review summarizes current literature on relationships between adipose tissue distribution and cognition in preclinical models and highlights unanswered questions surrounding the potential role of tissue- and cell type-specific insulin resistance in these effects. While gaps in knowledge persist related to insulin insensitivity and cognitive impairment in obesity, several recent studies suggest that cells of the neurovascular unit contribute to hippocampal synaptic dysfunction, and this review interprets those findings in the context of progressive metabolic dysfunction in the CNS. Signalling between cerebrovascular endothelial cells, astrocytes, microglia, and neurons has been linked with memory deficits in visceral obesity, and this article describes the cellular changes in each of these populations with respect to their role in amplification or diminution of peripheral signals. The picture emerging from these studies, while incomplete, implicates pro-inflammatory cytokines, insulin resistance, and hyperglycemia in various stages of obesity-induced hippocampal dysfunction. As in the parable of the five blind wanderers holding different parts of an elephant, considerable work remains in order to assemble a model for the underlying mechanisms linking visceral adiposity with age-related cognitive decline.
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Affiliation(s)
- Alexis M Stranahan
- Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, 1462 Laney Walker Blvd, Augusta, GA, 30912, USA.
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38
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Porniece Kumar M, Cremer AL, Klemm P, Steuernagel L, Sundaram S, Jais A, Hausen AC, Tao J, Secher A, Pedersen TÅ, Schwaninger M, Wunderlich FT, Lowell BB, Backes H, Brüning JC. Insulin signalling in tanycytes gates hypothalamic insulin uptake and regulation of AgRP neuron activity. Nat Metab 2021; 3:1662-1679. [PMID: 34931084 PMCID: PMC8688146 DOI: 10.1038/s42255-021-00499-0] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Accepted: 10/26/2021] [Indexed: 12/02/2022]
Abstract
Insulin acts on neurons and glial cells to regulate systemic glucose metabolism and feeding. However, the mechanisms of insulin access in discrete brain regions are incompletely defined. Here we show that insulin receptors in tanycytes, but not in brain endothelial cells, are required to regulate insulin access to the hypothalamic arcuate nucleus. Mice lacking insulin receptors in tanycytes (IR∆Tan mice) exhibit systemic insulin resistance, while displaying normal food intake and energy expenditure. Tanycytic insulin receptors are also necessary for the orexigenic effects of ghrelin, but not for the anorexic effects of leptin. IR∆Tan mice exhibit increased agouti-related peptide (AgRP) neuronal activity, while displaying blunted AgRP neuronal adaptations to feeding-related stimuli. Lastly, a highly palatable food decreases tanycytic and arcuate nucleus insulin signalling to levels comparable to those seen in IR∆Tan mice. These changes are rooted in modifications of cellular stress responses and of mitochondrial protein quality control in tanycytes. Conclusively, we reveal a critical role of tanycyte insulin receptors in gating feeding-state-dependent regulation of AgRP neurons and systemic insulin sensitivity, and show that insulin resistance in tanycytes contributes to the pleiotropic manifestations of obesity-associated insulin resistance.
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Affiliation(s)
- Marta Porniece Kumar
- Department of Neuronal Control of Metabolism, Max Planck Institute for Metabolism Research, Cologne, Germany
| | - Anna Lena Cremer
- Department of Neuronal Control of Metabolism, Max Planck Institute for Metabolism Research, Cologne, Germany
| | - Paul Klemm
- Department of Neuronal Control of Metabolism, Max Planck Institute for Metabolism Research, Cologne, Germany
| | - Lukas Steuernagel
- Department of Neuronal Control of Metabolism, Max Planck Institute for Metabolism Research, Cologne, Germany
| | - Sivaraj Sundaram
- Institute for Experimental and Clinical Pharmacology and Toxicology, University of Lübeck, Lübeck, Germany
| | - Alexander Jais
- Department of Neuronal Control of Metabolism, Max Planck Institute for Metabolism Research, Cologne, Germany
- Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG) of the Helmholtz Zentrum München at the University of Leipzig and University Hospital Leipzig, Leipzig, Germany
| | - A Christine Hausen
- Department of Neuronal Control of Metabolism, Max Planck Institute for Metabolism Research, Cologne, Germany
| | - Jenkang Tao
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
- Program in Neuroscience, Harvard Medical School, Boston, MA, USA
| | - Anna Secher
- Global Drug Discovery, Novo Nordisk A/S, Måløv, Denmark
| | | | - Markus Schwaninger
- Institute for Experimental and Clinical Pharmacology and Toxicology, University of Lübeck, Lübeck, Germany
| | - F Thomas Wunderlich
- Department of Neuronal Control of Metabolism, Max Planck Institute for Metabolism Research, Cologne, Germany
| | - Bradford B Lowell
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
- Program in Neuroscience, Harvard Medical School, Boston, MA, USA
| | - Heiko Backes
- Department of Neuronal Control of Metabolism, Max Planck Institute for Metabolism Research, Cologne, Germany
| | - Jens C Brüning
- Department of Neuronal Control of Metabolism, Max Planck Institute for Metabolism Research, Cologne, Germany.
- Policlinic for Endocrinology, Diabetes and Preventive Medicine (CEDP), University Hospital Cologne, Cologne, Germany.
- National Center for Diabetes Research (DZD), Neuherberg, Germany.
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Milstein JL, Ferris HA. The brain as an insulin-sensitive metabolic organ. Mol Metab 2021; 52:101234. [PMID: 33845179 PMCID: PMC8513144 DOI: 10.1016/j.molmet.2021.101234] [Citation(s) in RCA: 110] [Impact Index Per Article: 27.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Revised: 03/26/2021] [Accepted: 04/07/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The brain was once thought of as an insulin-insensitive organ. We now know that the insulin receptor is present throughout the brain and serves important functions in whole-body metabolism and brain function. Brain insulin signaling is involved not only in brain homeostatic processes but also neuropathological processes such as cognitive decline and Alzheimer's disease. SCOPE OF REVIEW In this review, we provide an overview of insulin signaling within the brain and the metabolic impact of brain insulin resistance and discuss Alzheimer's disease, one of the neurologic diseases most closely associated with brain insulin resistance. MAJOR CONCLUSIONS While brain insulin signaling plays only a small role in central nervous system glucose regulation, it has a significant impact on the brain's metabolic health. Normal insulin signaling is important for mitochondrial functioning and normal food intake. Brain insulin resistance contributes to obesity and may also play an important role in neurodegeneration.
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Affiliation(s)
- Joshua L Milstein
- Center for Brain Immunology and Glia, University of Virginia, Charlottesville, VA, USA; Department of Neuroscience, University of Virginia, Charlottesville, VA, USA
| | - Heather A Ferris
- Center for Brain Immunology and Glia, University of Virginia, Charlottesville, VA, USA; Department of Neuroscience, University of Virginia, Charlottesville, VA, USA; Division of Endocrinology and Metabolism, University of Virginia, Charlottesville, VA, USA.
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40
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Rhea EM, Hansen K, Pemberton S, Torres ERS, Holden S, Raber J, Banks WA. Effects of apolipoprotein E isoform, sex, and diet on insulin BBB pharmacokinetics in mice. Sci Rep 2021; 11:18636. [PMID: 34545146 PMCID: PMC8452709 DOI: 10.1038/s41598-021-98061-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Accepted: 09/02/2021] [Indexed: 11/26/2022] Open
Abstract
Age, apolipoprotein E (apoE) isoform, sex, and diet can independently affect the risk for the development of Alzheimer’s disease (AD). Additionally, synergy between some of these risk factors have been observed. However, the relation between the latter three risk factors has not been investigated. Central nervous system (CNS) insulin resistance is commonly involved in each of these risk factors. CNS insulin is primarily derived from the periphery in which insulin must be transported across the blood–brain barrier (BBB). Additionally, insulin can bind the brain endothelial cell to affect intracellular signaling. Therefore, we hypothesized CNS access to insulin could be affected by the combination of apoE isoform, sex, and diet. We analyzed insulin BBB pharmacokinetics in aged apoE targeted replacement (E3 and E4) male and female mice on a low-fat and high-fat diet. There were differences within males and females due to apoE genotype and diet in insulin interactions at the BBB. These sex-, diet-, and apoE isoform-dependent differences could contribute to the cognitive changes observed due to altered CNS insulin signaling.
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Affiliation(s)
- Elizabeth M Rhea
- Department of Medicine, Division of Gerontology and Geriatric Medicine, University of Washington, Seattle, WA, 98195, USA. .,Geriatric Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA, 98108, USA.
| | - Kim Hansen
- Geriatric Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA, 98108, USA
| | - Sarah Pemberton
- Geriatric Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA, 98108, USA
| | - Eileen Ruth S Torres
- Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR, 97239, USA
| | - Sarah Holden
- Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR, 97239, USA
| | - Jacob Raber
- Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR, 97239, USA.,Division of Neuroscience, Departments of Neurology and Radiation Medicine, ONPRC, Oregon Health & Science University, Portland, OR, 97239, USA
| | - William A Banks
- Department of Medicine, Division of Gerontology and Geriatric Medicine, University of Washington, Seattle, WA, 98195, USA.,Geriatric Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA, 98108, USA
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41
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Scherer T, Sakamoto K, Buettner C. Brain insulin signalling in metabolic homeostasis and disease. Nat Rev Endocrinol 2021; 17:468-483. [PMID: 34108679 DOI: 10.1038/s41574-021-00498-x] [Citation(s) in RCA: 92] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/22/2021] [Indexed: 02/06/2023]
Abstract
Insulin signalling in the central nervous system regulates energy homeostasis by controlling metabolism in several organs and by coordinating organ crosstalk. Studies performed in rodents, non-human primates and humans over more than five decades using intracerebroventricular, direct hypothalamic or intranasal application of insulin provide evidence that brain insulin action might reduce food intake and, more importantly, regulates energy homeostasis by orchestrating nutrient partitioning. This Review discusses the metabolic pathways that are under the control of brain insulin action and explains how brain insulin resistance contributes to metabolic disease in obesity, the metabolic syndrome and type 2 diabetes mellitus.
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Affiliation(s)
- Thomas Scherer
- Division of Endocrinology and Metabolism, Department of Medicine III, Medical University of Vienna, Vienna, Austria.
| | - Kenichi Sakamoto
- Division of Endocrinology, Metabolism & Nutrition, Department of Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA
| | - Christoph Buettner
- Division of Endocrinology, Metabolism & Nutrition, Department of Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA.
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42
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Islam Y, Leach AG, Smith J, Pluchino S, Coxon CR, Sivakumaran M, Downing J, Fatokun AA, Teixidò M, Ehtezazi T. Physiological and Pathological Factors Affecting Drug Delivery to the Brain by Nanoparticles. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2021; 8:e2002085. [PMID: 34105297 PMCID: PMC8188209 DOI: 10.1002/advs.202002085] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Revised: 01/06/2021] [Indexed: 05/04/2023]
Abstract
The prevalence of neurological/neurodegenerative diseases, such as Alzheimer's disease is known to be increasing due to an aging population and is anticipated to further grow in the decades ahead. The treatment of brain diseases is challenging partly due to the inaccessibility of therapeutic agents to the brain. An increasingly important observation is that the physiology of the brain alters during many brain diseases, and aging adds even more to the complexity of the disease. There is a notion that the permeability of the blood-brain barrier (BBB) increases with aging or disease, however, the body has a defense mechanism that still retains the separation of the brain from harmful chemicals in the blood. This makes drug delivery to the diseased brain, even more challenging and complex task. Here, the physiological changes to the diseased brain and aged brain are covered in the context of drug delivery to the brain using nanoparticles. Also, recent and novel approaches are discussed for the delivery of therapeutic agents to the diseased brain using nanoparticle based or magnetic resonance imaging guided systems. Furthermore, the complement activation, toxicity, and immunogenicity of brain targeting nanoparticles as well as novel in vitro BBB models are discussed.
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Affiliation(s)
- Yamir Islam
- School of Pharmacy and Biomolecular SciencesLiverpool John Moores UniversityByrom StreetLiverpoolL3 3AFUK
| | - Andrew G. Leach
- School of Pharmacy and Biomolecular SciencesLiverpool John Moores UniversityByrom StreetLiverpoolL3 3AFUK
- Division of Pharmacy and OptometryThe University of ManchesterStopford Building, Oxford RoadManchesterM13 9PTUK
| | - Jayden Smith
- Cambridge Innovation Technologies Consulting (CITC) LimitedSt. John's Innovation CentreCowley RoadCambridgeCB4 0WSUK
| | - Stefano Pluchino
- Department of Clinical NeurosciencesClifford Allbutt Building – Cambridge Biosciences Campus and NIHR Biomedical Research CentreUniversity of CambridgeHills RoadCambridgeCB2 0HAUK
| | - Christopher R. Coxon
- School of Pharmacy and Biomolecular SciencesLiverpool John Moores UniversityByrom StreetLiverpoolL3 3AFUK
- School of Engineering and Physical SciencesHeriot‐Watt UniversityWilliam Perkin BuildingEdinburghEH14 4ASUK
| | - Muttuswamy Sivakumaran
- Department of HaematologyPeterborough City HospitalEdith Cavell CampusBretton Gate PeterboroughPeterboroughPE3 9GZUK
| | - James Downing
- School of Pharmacy and Biomolecular SciencesLiverpool John Moores UniversityByrom StreetLiverpoolL3 3AFUK
| | - Amos A. Fatokun
- School of Pharmacy and Biomolecular SciencesLiverpool John Moores UniversityByrom StreetLiverpoolL3 3AFUK
| | - Meritxell Teixidò
- Institute for Research in Biomedicine (IRB Barcelona)Barcelona Institute of Science and Technology (BIST)Baldiri Reixac 10Barcelona08028Spain
| | - Touraj Ehtezazi
- School of Pharmacy and Biomolecular SciencesLiverpool John Moores UniversityByrom StreetLiverpoolL3 3AFUK
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Alves SS, Silva-Junior RMPD, Servilha-Menezes G, Homolak J, Šalković-Petrišić M, Garcia-Cairasco N. Insulin Resistance as a Common Link Between Current Alzheimer's Disease Hypotheses. J Alzheimers Dis 2021; 82:71-105. [PMID: 34024838 DOI: 10.3233/jad-210234] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Almost 115 years ago, Alois Alzheimer described Alzheimer's disease (AD) for the first time. Since then, many hypotheses have been proposed. However, AD remains a severe health public problem. The current medical approaches for AD are limited to symptomatic interventions and the complexity of this disease has led to a failure rate of approximately 99.6%in AD clinical trials. In fact, no new drug has been approved for AD treatment since 2003. These failures indicate that we are failing in mimicking this disease in experimental models. Although most studies have focused on the amyloid cascade hypothesis of AD, the literature has made clear that AD is rather a multifactorial disorder. Therefore, the persistence in a single theory has resulted in lost opportunities. In this review, we aim to present the striking points of the long scientific path followed since the description of the first AD case and the main AD hypotheses discussed over the last decades. We also propose insulin resistance as a common link between many other hypotheses.
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Affiliation(s)
- Suélen Santos Alves
- Department of Neurosciences and Behavioral Sciences, Ribeirão Preto Medical School - University of São Paulo (FMRP-USP), Ribeirão Preto, São Paulo, Brazil
| | - Rui Milton Patrício da Silva-Junior
- Department of Internal Medicine, Ribeirão Preto Medical School -University of São Paulo (FMRP-USP), Ribeirão Preto, São Paulo, Brazil.,Department of Physiology, Ribeirão Preto Medical School - University of São Paulo (FMRP-USP), Ribeirão Preto, São Paulo, Brazil
| | - Gabriel Servilha-Menezes
- Department of Physiology, Ribeirão Preto Medical School - University of São Paulo (FMRP-USP), Ribeirão Preto, São Paulo, Brazil
| | - Jan Homolak
- Department of Pharmacology, University of Zagreb School of Medicine, Zagreb, Croatia.,Croatian Institute for Brain Research, University of Zagreb School of Medicine, Zagreb, Croatia
| | - Melita Šalković-Petrišić
- Department of Pharmacology, University of Zagreb School of Medicine, Zagreb, Croatia.,Croatian Institute for Brain Research, University of Zagreb School of Medicine, Zagreb, Croatia
| | - Norberto Garcia-Cairasco
- Department of Neurosciences and Behavioral Sciences, Ribeirão Preto Medical School - University of São Paulo (FMRP-USP), Ribeirão Preto, São Paulo, Brazil.,Department of Physiology, Ribeirão Preto Medical School - University of São Paulo (FMRP-USP), Ribeirão Preto, São Paulo, Brazil
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44
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Zhao J, Imai R, Ukon N, Shimoyama S, Tan C, Maejima Y, Omiya Y, Takahashi K, Nan G, Zhao S, Ito H, Shimomura K. Evaluation of Effect of Ninjin'yoeito on Regional Brain Glucose Metabolism by 18F-FDG Autoradiography With Insulin Loading in Aged Mice. Front Nutr 2021; 8:657663. [PMID: 34055854 PMCID: PMC8152663 DOI: 10.3389/fnut.2021.657663] [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: 01/23/2021] [Accepted: 03/16/2021] [Indexed: 12/02/2022] Open
Abstract
Introduction: A recent clinical study revealed that Ninjin'yoeito (NYT) may potentially improve cognitive outcome. However, the mechanism by which NYT exerts its effect on elderly patients remains unclear. The aim of this study is to evaluate the effect of Ninjin'yoeito on regional brain glucose metabolism by 18F-FDG autoradiography with insulin loading in aged wild-type mice. Materials and Methods: After 12 weeks of feeding NYT, mice were assigned to the control and insulin-loaded groups and received an intraperitoneal injection of human insulin (2 U/kg body weight) 30 min prior to 18F-FDG injection. Ninety minutes after the injection, brain autoradiography was performed. Results: After insulin loading, the 18F-FDG accumulation showed negative changes in the cortex, striatum, thalamus, and hippocampus in the control group, whereas positive changes were observed in the NYT-treated group. Conclusions: Ninjin'yoeito may potentially reduce insulin resistance in the brain regions in aged mice, thereby preventing age-related brain diseases.
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Affiliation(s)
- Jingmin Zhao
- Department of Neurology, China-Japan Union Hospital of Jilin University, Changchun, China.,Department of Radiology and Nuclear Medicine, Fukushima Medical University, Fukushima, Japan
| | - Ryota Imai
- Tsumura Kampo Research Laboratories, Kampo Research and Development Division, Tsumura & Co., Ibaraki, Japan.,Department of Bioregulation and Pharmacological Medicine, Fukushima Medical University, Fukushima, Japan
| | - Naoyuki Ukon
- Advanced Clinical Research Center, Fukushima Global Medical Science Center, Fukushima Medical University, Fukushima, Japan
| | - Saki Shimoyama
- Advanced Clinical Research Center, Fukushima Global Medical Science Center, Fukushima Medical University, Fukushima, Japan
| | - Chengbo Tan
- Advanced Clinical Research Center, Fukushima Global Medical Science Center, Fukushima Medical University, Fukushima, Japan.,Department of Neurosurgery, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Yuko Maejima
- Department of Bioregulation and Pharmacological Medicine, Fukushima Medical University, Fukushima, Japan
| | - Yuji Omiya
- Tsumura Kampo Research Laboratories, Kampo Research and Development Division, Tsumura & Co., Ibaraki, Japan
| | - Kazuhiro Takahashi
- Advanced Clinical Research Center, Fukushima Global Medical Science Center, Fukushima Medical University, Fukushima, Japan
| | - Guangxian Nan
- Department of Neurology, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Songji Zhao
- Advanced Clinical Research Center, Fukushima Global Medical Science Center, Fukushima Medical University, Fukushima, Japan.,Department of Pathophysiology, Basic Medical College of Jilin University, Changchun, China
| | - Hiroshi Ito
- Department of Radiology and Nuclear Medicine, Fukushima Medical University, Fukushima, Japan.,Advanced Clinical Research Center, Fukushima Global Medical Science Center, Fukushima Medical University, Fukushima, Japan
| | - Kenju Shimomura
- Department of Bioregulation and Pharmacological Medicine, Fukushima Medical University, Fukushima, Japan
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45
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Dos Santos KM, Moraes DJDA, da Silva MP, Antunes VR. Exercise training rescues the electrical activity of liver-projecting DMNV neurones in response to oxytocin in spontaneously hypertensive rats. J Neuroendocrinol 2021; 33:e12977. [PMID: 33942389 DOI: 10.1111/jne.12977] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2020] [Revised: 03/30/2021] [Accepted: 04/02/2021] [Indexed: 12/15/2022]
Abstract
A neural circuit between the paraventricular nucleus of the hypothalamus (PVN) and the dorsal motor nucleus of the vagus (DMNV) constitutes part of an important parasympathetic autonomic pathway that controls hepatic glucose production. Intracerebroventricular injection of insulin activates oxytocinergic neurones in the PVN and elicits the release of oxytocin into the circulation, which plays an important role in the metabolism of glucose. Moreover, the central action of insulin can reduce the concentration of glucose in blood taken from the hepatic vein of Wistar rats via activation of vagal efferent nerves to the liver. This mechanism is impaired in sedentary spontaneously hypertensive rats (SHR). Because aerobic exercise increases vagal tone, partly mediated by increasing the oxytocinergic connections between the PVN and DMNV, we hypothesised that oxytocin (OT) might alter the excitability of liver-projecting DMNV neurones. Thus, we investigated the effects of OT on electrical properties of the liver-projecting DMNV neurones from Wistar, SHR subjected to 4 weeks of exercise training, as well sedentary controls, using whole cell patch-clamping. The results show that OT increased the resting membrane potential of DMNV neurones in Wistar rats, as well as the firing frequency of these cells, but not in sedentary SHR. However, in SHR subjected to 4 weeks of exercise training, the effects of OT on liver-projecting DMNV neurones of were similar to those seen in Wistar rats. These findings show that OT elicits similar changes in the electrophysiological properties of liver-projecting DMNV neurones of Wistar and exercise-trained but not sedentary SHR. These results indicate that exercise training can restore the sensitivity of liver-projecting DMNV neurones of exercise-trained SHR to OT.
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Affiliation(s)
- Karoline Martins Dos Santos
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil
| | - Davi José de Almeida Moraes
- Department of Physiology, School of Medicine of Ribeirao Preto, University of Sao Paulo, Ribeirao Preto, Brazil
| | - Melina Pires da Silva
- Department of Physiology, School of Medicine of Ribeirao Preto, University of Sao Paulo, Ribeirao Preto, Brazil
| | - Vagner Roberto Antunes
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil
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46
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Mitchell CS, Begg DP. The regulation of food intake by insulin in the central nervous system. J Neuroendocrinol 2021; 33:e12952. [PMID: 33656205 DOI: 10.1111/jne.12952] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2020] [Revised: 01/31/2021] [Accepted: 02/03/2021] [Indexed: 01/02/2023]
Abstract
Food intake and energy expenditure are regulated by peripheral signals providing feedback on nutrient status and adiposity to the central nervous system. One of these signals is the pancreatic hormone, insulin. Unlike peripheral administration of insulin, which often causes weight gain, central administration of insulin leads to a reduction in food intake and body weight when administered long-term. This is a result of feedback processes in regions of the brain that regulate food intake. Within the hypothalamus, the arcuate nucleus (ARC) contains subpopulations of neurones that produce orexinergic neuropeptides agouti-related peptide (AgRP)/neuropeptide Y (NPY) and anorexigenic neuropeptides, pro-opiomelanocortin (POMC)/cocaine- and amphetamine-regulated transcript (CART). Intracerebroventricular infusion of insulin down-regulates the expression of AgRP/NPY at the same time as up-regulating expression of POMC/CART. Recent evidence suggests that insulin activity within the amygdala may play an important role in regulating energy balance. Insulin infusion into the central nucleus of the amygdala (CeA) can decrease food intake, possibly by modulating activity of NPY and other neurone subpopulations. Insulin signalling within the CeA can also influence stress-induced obesity. Overall, it is evident that the CeA is a critical target for insulin signalling and the regulation of energy balance.
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Affiliation(s)
| | - Denovan P Begg
- School of Psychology, UNSW Sydney, Sydney, NSW, Australia
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47
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Beddows CA, Dodd GT. Insulin on the brain: The role of central insulin signalling in energy and glucose homeostasis. J Neuroendocrinol 2021; 33:e12947. [PMID: 33687120 DOI: 10.1111/jne.12947] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2020] [Revised: 01/26/2021] [Accepted: 01/28/2021] [Indexed: 12/26/2022]
Abstract
Insulin signals to the brain where it coordinates multiple physiological processes underlying energy and glucose homeostasis. This review explores where and how insulin interacts within the brain parenchyma, how brain insulin signalling functions to coordinate energy and glucose homeostasis and how this contributes to the pathogenesis of metabolic disease.
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Affiliation(s)
- Cait A Beddows
- Department of Anatomy and Physiology, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Melbourne, VIC, Australia
| | - Garron T Dodd
- Department of Anatomy and Physiology, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Melbourne, VIC, Australia
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48
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Rhea EM, Banks WA. A historical perspective on the interactions of insulin at the blood-brain barrier. J Neuroendocrinol 2021; 33:e12929. [PMID: 33433042 PMCID: PMC8052275 DOI: 10.1111/jne.12929] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2020] [Revised: 11/18/2020] [Accepted: 12/02/2020] [Indexed: 11/30/2022]
Abstract
Subsequent to the discovery of insulin in 1921, the role of insulin in the brain has been investigated throughly. The ability of insulin to act within the brain to regulate peripheral glucose levels helped evolve the research surrounding the ability of insulin to be transported into the brain. Investigations aiming to determine the transport of insulin into the brain from the circulation soon followed. Once it was established that insulin could enter the brain, the ability of insulin to bind brain microvessels and regulators of this process were determined. As technology advanced, quantitative measurements to specify the transport rate of insulin across the blood-brain barrier (BBB) and the impact of physiological conditions and diseases were the logical next steps. Lastly, with the advent of genetic mouse models and high-specificity antagonists, the specific role of the insulin receptor in mediating insulin transport could begin to be explored. In this review, we summarise the main findings throughout the decades regarding the interactions of insulin at the BBB.
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Affiliation(s)
- Elizabeth M. Rhea
- Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington School of Medicine, Seattle, Washington, USA 98159
- Geriatrics Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, 1660 S Columbian Way, Seattle, Washington, USA 98108
- Corresponding author: Elizabeth M. Rhea;
| | - William A. Banks
- Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington School of Medicine, Seattle, Washington, USA 98159
- Geriatrics Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, 1660 S Columbian Way, Seattle, Washington, USA 98108
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49
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Jaszczyk A, Juszczak GR. Glucocorticoids, metabolism and brain activity. Neurosci Biobehav Rev 2021; 126:113-145. [PMID: 33727030 DOI: 10.1016/j.neubiorev.2021.03.007] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2020] [Revised: 03/04/2021] [Accepted: 03/07/2021] [Indexed: 12/17/2022]
Abstract
The review integrates different experimental approaches including biochemistry, c-Fos expression, microdialysis (glutamate, GABA, noradrenaline and serotonin), electrophysiology and fMRI to better understand the effect of elevated level of glucocorticoids on the brain activity and metabolism. The available data indicate that glucocorticoids alter the dynamics of neuronal activity leading to context-specific changes including both excitation and inhibition and these effects are expected to support the task-related responses. Glucocorticoids also lead to diversification of available sources of energy due to elevated levels of glucose, lactate, pyruvate, mannose and hydroxybutyrate (ketone bodies), which can be used to fuel brain, and facilitate storage and utilization of brain carbohydrate reserves formed by glycogen. However, the mismatch between carbohydrate supply and utilization that is most likely to occur in situations not requiring energy-consuming activities lead to metabolic stress due to elevated brain levels of glucose. Excessive doses of glucocorticoids also impair the production of energy (ATP) and mitochondrial oxidation. Therefore, glucocorticoids have both adaptive and maladaptive effects consistently with the concept of allostatic load and overload.
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Affiliation(s)
- Aneta Jaszczyk
- Department of Animal Behavior and Welfare, Institute of Genetics and Animal Biotechnology, Polish Academy of Sciences, 05-552 Jastrzebiec, 36a Postepu str., Poland
| | - Grzegorz R Juszczak
- Department of Animal Behavior and Welfare, Institute of Genetics and Animal Biotechnology, Polish Academy of Sciences, 05-552 Jastrzebiec, 36a Postepu str., Poland.
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50
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Woods B, Silva RDM, Schmidt C, Wragg D, Cavaco M, Neves V, Ferreira VFC, Gano L, Morais TS, Mendes F, Correia JDG, Casini A. Bioconjugate Supramolecular Pd 2+ Metallacages Penetrate the Blood Brain Barrier In Vitro and In Vivo. Bioconjug Chem 2021; 32:1399-1408. [PMID: 33440122 DOI: 10.1021/acs.bioconjchem.0c00659] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
The biomedical application of discrete supramolecular metal-based structures, specifically self-assembled metallacages, is still an emergent field of study. Capitalizing on the knowledge gained in recent years on the development of 3-dimensional (3D) metallacages as novel drug delivery systems and theranostic agents, we explore here the possibility to target [Pd2L4]4+ cages (L = 3,5-bis(3-ethynylpyridine)phenyl ligand) to the brain. In detail, a new water-soluble homoleptic cage (CPepH3) tethered to a blood brain barrier (BBB)-translocating peptide was synthesized by a combination of solid-phase peptide synthesis (SPPS) and self-assembly procedures. The cage translocation efficacy was assessed by inductively coupled mass spectrometry (ICP-MS) in a BBB cellular model in vitro. Biodistribution studies of the radiolabeled cage [[99mTcO4]- ⊂ CPepH3] in the CD1 mice model demonstrate its brain penetration properties in vivo. Further DFT studies were conducted to model the structure of the [[99mTcO4]- ⊂ cage] complex. Moreover, the encapsulation capabilities and stability of the cage were investigated using the [ReO4]- anion, the "cold" analogue of [99mTcO4]-, by 1H NMR spectroscopy. Overall, our study constitutes another proof-of-concept of the unique potential of supramolecular coordination complexes for modifying the physiochemical and biodistribution properties of diagnostic species.
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Affiliation(s)
- Ben Woods
- Institute of Structural and Molecular Biology and Department of Biological Sciences, School of Science, Birkbeck University of London, Malet Street, London WC1E 7HX, United Kingdom
| | - Rúben D M Silva
- Centro de Ciências e Tecnologias Nucleares (C2TN), Instituto Superior Técnico, Universidade de Lisboa Estrada Nacional 10, 2695-066 Bobadela, LRS, Portugal
| | - Claudia Schmidt
- Department of Chemistry, Technical University of Munich, Lichtenbergstrasse 4, 85748 Garching bei München, Germany
| | - Darren Wragg
- Department of Chemistry, Technical University of Munich, Lichtenbergstrasse 4, 85748 Garching bei München, Germany
| | - Marco Cavaco
- Instituto de Medicina Molecular João Lobo Antunes (iMM-JLA), Faculdade de Medicina, Universidade de Lisboa, Av. Prof. Egas Moniz, 1649-028 Lisboa, Portugal
| | - Vera Neves
- Instituto de Medicina Molecular João Lobo Antunes (iMM-JLA), Faculdade de Medicina, Universidade de Lisboa, Av. Prof. Egas Moniz, 1649-028 Lisboa, Portugal
| | - Vera F C Ferreira
- Centro de Ciências e Tecnologias Nucleares (C2TN), Instituto Superior Técnico, Universidade de Lisboa Estrada Nacional 10, 2695-066 Bobadela, LRS, Portugal
| | - Lurdes Gano
- Centro de Ciências e Tecnologias Nucleares (C2TN), Instituto Superior Técnico, Universidade de Lisboa Estrada Nacional 10, 2695-066 Bobadela, LRS, Portugal.,Departamento de Engenharia e Ciências Nucleares (DECN), Instituto Superior Técnico, Universidade de Lisboa, Estrada Nacional 10, 2695-066 Bobadela, LRS, Portugal
| | - Tânia S Morais
- Centro de Química Estrutural and Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade de Lisboa, Campo Grande, 1749-016 Lisboa, Portugal
| | - Filipa Mendes
- Centro de Ciências e Tecnologias Nucleares (C2TN), Instituto Superior Técnico, Universidade de Lisboa Estrada Nacional 10, 2695-066 Bobadela, LRS, Portugal.,Departamento de Engenharia e Ciências Nucleares (DECN), Instituto Superior Técnico, Universidade de Lisboa, Estrada Nacional 10, 2695-066 Bobadela, LRS, Portugal
| | - João D G Correia
- Centro de Ciências e Tecnologias Nucleares (C2TN), Instituto Superior Técnico, Universidade de Lisboa Estrada Nacional 10, 2695-066 Bobadela, LRS, Portugal.,Departamento de Engenharia e Ciências Nucleares (DECN), Instituto Superior Técnico, Universidade de Lisboa, Estrada Nacional 10, 2695-066 Bobadela, LRS, Portugal
| | - Angela Casini
- Department of Chemistry, Technical University of Munich, Lichtenbergstrasse 4, 85748 Garching bei München, Germany
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