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Resveratrol Preconditioning Protects Against Ischemia-Induced Synaptic Dysfunction and Cofilin Hyperactivation in the Mouse Hippocampal Slice

Perturbations in synaptic function are major determinants of several neurological diseases and have been associated with cognitive impairments after cerebral ischemia (CI). Although the mechanisms underlying CI-induced synaptic dysfunction have not been well defined, evidence suggests that early hyp...

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Autores principales: Escobar, Iris, Xu, Jing, Jackson, Charles W., Stegelmann, Samuel D., Fagerli, Eric A., Dave, Kunjan R., Perez-Pinzon, Miguel A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer International Publishing 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10457274/
https://www.ncbi.nlm.nih.gov/pubmed/37208551
http://dx.doi.org/10.1007/s13311-023-01386-0
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author Escobar, Iris
Xu, Jing
Jackson, Charles W.
Stegelmann, Samuel D.
Fagerli, Eric A.
Dave, Kunjan R.
Perez-Pinzon, Miguel A.
author_facet Escobar, Iris
Xu, Jing
Jackson, Charles W.
Stegelmann, Samuel D.
Fagerli, Eric A.
Dave, Kunjan R.
Perez-Pinzon, Miguel A.
author_sort Escobar, Iris
collection PubMed
description Perturbations in synaptic function are major determinants of several neurological diseases and have been associated with cognitive impairments after cerebral ischemia (CI). Although the mechanisms underlying CI-induced synaptic dysfunction have not been well defined, evidence suggests that early hyperactivation of the actin-binding protein, cofilin, plays a role. Given that synaptic impairments manifest shortly after CI, prophylactic strategies may offer a better approach to prevent/mitigate synaptic damage following an ischemic event. Our laboratory has previously demonstrated that resveratrol preconditioning (RPC) promotes cerebral ischemic tolerance, with many groups highlighting beneficial effects of resveratrol treatment on synaptic and cognitive function in other neurological conditions. Herein, we hypothesized that RPC would mitigate hippocampal synaptic dysfunction and pathological cofilin hyperactivation in an ex vivo model of ischemia. Various electrophysiological parameters and synaptic-related protein expression changes were measured under normal and ischemic conditions utilizing acute hippocampal slices derived from adult male mice treated with resveratrol (10 mg/kg) or vehicle 48 h prior. Remarkably, RPC significantly increased the latency to anoxic depolarization, decreased cytosolic calcium accumulation, prevented aberrant increases in synaptic transmission, and rescued deficits in long-term potentiation following ischemia. Additionally, RPC upregulated the expression of the activity-regulated cytoskeleton associated protein, Arc, which was partially required for RPC-mediated attenuation of cofilin hyperactivation. Taken together, these findings support a role for RPC in mitigating CI-induced excitotoxicity, synaptic dysfunction, and pathological over-activation of cofilin. Our study provides further insight into mechanisms underlying RPC-mediated neuroprotection against CI and implicates RPC as a promising strategy to preserve synaptic function after ischemia. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13311-023-01386-0.
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spelling pubmed-104572742023-08-27 Resveratrol Preconditioning Protects Against Ischemia-Induced Synaptic Dysfunction and Cofilin Hyperactivation in the Mouse Hippocampal Slice Escobar, Iris Xu, Jing Jackson, Charles W. Stegelmann, Samuel D. Fagerli, Eric A. Dave, Kunjan R. Perez-Pinzon, Miguel A. Neurotherapeutics Original Article Perturbations in synaptic function are major determinants of several neurological diseases and have been associated with cognitive impairments after cerebral ischemia (CI). Although the mechanisms underlying CI-induced synaptic dysfunction have not been well defined, evidence suggests that early hyperactivation of the actin-binding protein, cofilin, plays a role. Given that synaptic impairments manifest shortly after CI, prophylactic strategies may offer a better approach to prevent/mitigate synaptic damage following an ischemic event. Our laboratory has previously demonstrated that resveratrol preconditioning (RPC) promotes cerebral ischemic tolerance, with many groups highlighting beneficial effects of resveratrol treatment on synaptic and cognitive function in other neurological conditions. Herein, we hypothesized that RPC would mitigate hippocampal synaptic dysfunction and pathological cofilin hyperactivation in an ex vivo model of ischemia. Various electrophysiological parameters and synaptic-related protein expression changes were measured under normal and ischemic conditions utilizing acute hippocampal slices derived from adult male mice treated with resveratrol (10 mg/kg) or vehicle 48 h prior. Remarkably, RPC significantly increased the latency to anoxic depolarization, decreased cytosolic calcium accumulation, prevented aberrant increases in synaptic transmission, and rescued deficits in long-term potentiation following ischemia. Additionally, RPC upregulated the expression of the activity-regulated cytoskeleton associated protein, Arc, which was partially required for RPC-mediated attenuation of cofilin hyperactivation. Taken together, these findings support a role for RPC in mitigating CI-induced excitotoxicity, synaptic dysfunction, and pathological over-activation of cofilin. Our study provides further insight into mechanisms underlying RPC-mediated neuroprotection against CI and implicates RPC as a promising strategy to preserve synaptic function after ischemia. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13311-023-01386-0. Springer International Publishing 2023-05-19 2023-07 /pmc/articles/PMC10457274/ /pubmed/37208551 http://dx.doi.org/10.1007/s13311-023-01386-0 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Original Article
Escobar, Iris
Xu, Jing
Jackson, Charles W.
Stegelmann, Samuel D.
Fagerli, Eric A.
Dave, Kunjan R.
Perez-Pinzon, Miguel A.
Resveratrol Preconditioning Protects Against Ischemia-Induced Synaptic Dysfunction and Cofilin Hyperactivation in the Mouse Hippocampal Slice
title Resveratrol Preconditioning Protects Against Ischemia-Induced Synaptic Dysfunction and Cofilin Hyperactivation in the Mouse Hippocampal Slice
title_full Resveratrol Preconditioning Protects Against Ischemia-Induced Synaptic Dysfunction and Cofilin Hyperactivation in the Mouse Hippocampal Slice
title_fullStr Resveratrol Preconditioning Protects Against Ischemia-Induced Synaptic Dysfunction and Cofilin Hyperactivation in the Mouse Hippocampal Slice
title_full_unstemmed Resveratrol Preconditioning Protects Against Ischemia-Induced Synaptic Dysfunction and Cofilin Hyperactivation in the Mouse Hippocampal Slice
title_short Resveratrol Preconditioning Protects Against Ischemia-Induced Synaptic Dysfunction and Cofilin Hyperactivation in the Mouse Hippocampal Slice
title_sort resveratrol preconditioning protects against ischemia-induced synaptic dysfunction and cofilin hyperactivation in the mouse hippocampal slice
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10457274/
https://www.ncbi.nlm.nih.gov/pubmed/37208551
http://dx.doi.org/10.1007/s13311-023-01386-0
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