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Neuroprotective Effects and Treatment Potential of Incretin Mimetics in a Murine Model of Mild Traumatic Brain Injury

Traumatic brain injury (TBI) is a commonly occurring injury in sports, victims of motor vehicle accidents, and falls. TBI has become a pressing public health concern with no specific therapeutic treatment. Mild TBI (mTBI), which accounts for approximately 90% of all TBI cases, may frequently lead to...

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Autores principales: Bader, Miaad, Li, Yazhou, Tweedie, David, Shlobin, Nathan A., Bernstein, Adi, Rubovitch, Vardit, Tovar-y-Romo, Luis B., DiMarchi, Richard D., Hoffer, Barry J., Greig, Nigel H., Pick, Chaim G.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6965031/
https://www.ncbi.nlm.nih.gov/pubmed/31998717
http://dx.doi.org/10.3389/fcell.2019.00356
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author Bader, Miaad
Li, Yazhou
Tweedie, David
Shlobin, Nathan A.
Bernstein, Adi
Rubovitch, Vardit
Tovar-y-Romo, Luis B.
DiMarchi, Richard D.
Hoffer, Barry J.
Greig, Nigel H.
Pick, Chaim G.
author_facet Bader, Miaad
Li, Yazhou
Tweedie, David
Shlobin, Nathan A.
Bernstein, Adi
Rubovitch, Vardit
Tovar-y-Romo, Luis B.
DiMarchi, Richard D.
Hoffer, Barry J.
Greig, Nigel H.
Pick, Chaim G.
author_sort Bader, Miaad
collection PubMed
description Traumatic brain injury (TBI) is a commonly occurring injury in sports, victims of motor vehicle accidents, and falls. TBI has become a pressing public health concern with no specific therapeutic treatment. Mild TBI (mTBI), which accounts for approximately 90% of all TBI cases, may frequently lead to long-lasting cognitive, behavioral, and emotional impairments. The incretins glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are gastrointestinal hormones that induce glucose-dependent insulin secretion, promote β-cell proliferation, and enhance resistance to apoptosis. GLP-1 mimetics are marketed as treatments for type 2 diabetes mellitus (T2DM) and are well tolerated. Both GLP-1 and GIP mimetics have shown neuroprotective properties in animal models of Parkinson’s and Alzheimer’s disease. The aim of this study is to evaluate the potential neuroprotective effects of liraglutide, a GLP-1 analog, and twincretin, a dual GLP-1R/GIPR agonist, in a murine mTBI model. First, we subjected mice to mTBI using a weight-drop device and, thereafter, administered liraglutide or twincretin as a 7-day regimen of subcutaneous (s.c.) injections. We then investigated the effects of these drugs on mTBI-induced cognitive impairments, neurodegeneration, and neuroinflammation. Finally, we assessed their effects on neuroprotective proteins expression that are downstream to GLP-1R/GIPR activation; specifically, PI3K and PKA phosphorylation. Both drugs ameliorated mTBI-induced cognitive impairments evaluated by the novel object recognition (NOR) and the Y-maze paradigms in which neither anxiety nor locomotor activity were confounds, as the latter were unaffected by either mTBI or drugs. Additionally, both drugs significantly mitigated mTBI-induced neurodegeneration and neuroinflammation, as quantified by immunohistochemical staining with Fluoro-Jade/anti-NeuN and anti-Iba-1 antibodies, respectively. mTBI challenge significantly decreased PKA phosphorylation levels in ipsilateral cortex, which was mitigated by both drugs. However, PI3K phosphorylation was not affected by mTBI. These findings offer a new potential therapeutic approach to treat mTBI, and support further investigation of the neuroprotective effects and mechanism of action of incretin-based therapies for neurological disorders.
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spelling pubmed-69650312020-01-29 Neuroprotective Effects and Treatment Potential of Incretin Mimetics in a Murine Model of Mild Traumatic Brain Injury Bader, Miaad Li, Yazhou Tweedie, David Shlobin, Nathan A. Bernstein, Adi Rubovitch, Vardit Tovar-y-Romo, Luis B. DiMarchi, Richard D. Hoffer, Barry J. Greig, Nigel H. Pick, Chaim G. Front Cell Dev Biol Cell and Developmental Biology Traumatic brain injury (TBI) is a commonly occurring injury in sports, victims of motor vehicle accidents, and falls. TBI has become a pressing public health concern with no specific therapeutic treatment. Mild TBI (mTBI), which accounts for approximately 90% of all TBI cases, may frequently lead to long-lasting cognitive, behavioral, and emotional impairments. The incretins glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are gastrointestinal hormones that induce glucose-dependent insulin secretion, promote β-cell proliferation, and enhance resistance to apoptosis. GLP-1 mimetics are marketed as treatments for type 2 diabetes mellitus (T2DM) and are well tolerated. Both GLP-1 and GIP mimetics have shown neuroprotective properties in animal models of Parkinson’s and Alzheimer’s disease. The aim of this study is to evaluate the potential neuroprotective effects of liraglutide, a GLP-1 analog, and twincretin, a dual GLP-1R/GIPR agonist, in a murine mTBI model. First, we subjected mice to mTBI using a weight-drop device and, thereafter, administered liraglutide or twincretin as a 7-day regimen of subcutaneous (s.c.) injections. We then investigated the effects of these drugs on mTBI-induced cognitive impairments, neurodegeneration, and neuroinflammation. Finally, we assessed their effects on neuroprotective proteins expression that are downstream to GLP-1R/GIPR activation; specifically, PI3K and PKA phosphorylation. Both drugs ameliorated mTBI-induced cognitive impairments evaluated by the novel object recognition (NOR) and the Y-maze paradigms in which neither anxiety nor locomotor activity were confounds, as the latter were unaffected by either mTBI or drugs. Additionally, both drugs significantly mitigated mTBI-induced neurodegeneration and neuroinflammation, as quantified by immunohistochemical staining with Fluoro-Jade/anti-NeuN and anti-Iba-1 antibodies, respectively. mTBI challenge significantly decreased PKA phosphorylation levels in ipsilateral cortex, which was mitigated by both drugs. However, PI3K phosphorylation was not affected by mTBI. These findings offer a new potential therapeutic approach to treat mTBI, and support further investigation of the neuroprotective effects and mechanism of action of incretin-based therapies for neurological disorders. Frontiers Media S.A. 2020-01-10 /pmc/articles/PMC6965031/ /pubmed/31998717 http://dx.doi.org/10.3389/fcell.2019.00356 Text en Copyright © 2020 Bader, Li, Tweedie, Shlobin, Bernstein, Rubovitch, Tovar-y-Romo, DiMarchi, Hoffer, Greig and Pick. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Cell and Developmental Biology
Bader, Miaad
Li, Yazhou
Tweedie, David
Shlobin, Nathan A.
Bernstein, Adi
Rubovitch, Vardit
Tovar-y-Romo, Luis B.
DiMarchi, Richard D.
Hoffer, Barry J.
Greig, Nigel H.
Pick, Chaim G.
Neuroprotective Effects and Treatment Potential of Incretin Mimetics in a Murine Model of Mild Traumatic Brain Injury
title Neuroprotective Effects and Treatment Potential of Incretin Mimetics in a Murine Model of Mild Traumatic Brain Injury
title_full Neuroprotective Effects and Treatment Potential of Incretin Mimetics in a Murine Model of Mild Traumatic Brain Injury
title_fullStr Neuroprotective Effects and Treatment Potential of Incretin Mimetics in a Murine Model of Mild Traumatic Brain Injury
title_full_unstemmed Neuroprotective Effects and Treatment Potential of Incretin Mimetics in a Murine Model of Mild Traumatic Brain Injury
title_short Neuroprotective Effects and Treatment Potential of Incretin Mimetics in a Murine Model of Mild Traumatic Brain Injury
title_sort neuroprotective effects and treatment potential of incretin mimetics in a murine model of mild traumatic brain injury
topic Cell and Developmental Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6965031/
https://www.ncbi.nlm.nih.gov/pubmed/31998717
http://dx.doi.org/10.3389/fcell.2019.00356
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