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Knockdown of NRSF Alleviates Ischemic Brain Injury and Microvasculature Defects in Diabetic MCAO Mice

Diabetes is one of the well-established risk factors of stroke and is associated with a poor outcome in patients with stroke. Previous studies have shown that the expression of neuron restrictive silencer factor (NRSF) is elevated in diabetes as well as ischemic stroke. However, the role of NRSF in...

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Autores principales: He, Cheng-Feng, Xue, Wen-Jiao, Xu, Xiao-Die, Wang, Jian-Tao, Wang, Xin-Ru, Feng, Yi, Zhou, Hou-Guang, Guo, Jing-Chun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9136417/
https://www.ncbi.nlm.nih.gov/pubmed/35645950
http://dx.doi.org/10.3389/fneur.2022.869220
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author He, Cheng-Feng
Xue, Wen-Jiao
Xu, Xiao-Die
Wang, Jian-Tao
Wang, Xin-Ru
Feng, Yi
Zhou, Hou-Guang
Guo, Jing-Chun
author_facet He, Cheng-Feng
Xue, Wen-Jiao
Xu, Xiao-Die
Wang, Jian-Tao
Wang, Xin-Ru
Feng, Yi
Zhou, Hou-Guang
Guo, Jing-Chun
author_sort He, Cheng-Feng
collection PubMed
description Diabetes is one of the well-established risk factors of stroke and is associated with a poor outcome in patients with stroke. Previous studies have shown that the expression of neuron restrictive silencer factor (NRSF) is elevated in diabetes as well as ischemic stroke. However, the role of NRSF in regulating an outcome of diabetic ischemic stroke has not been completely understood. Here, we hypothesized that diabetes-induced NRSF elevation can aggravate brain injury and cognition impairment in ischemic stroke. The diabetic ischemic stroke mice model was established by 8 weeks of high-fat-diet feeding and 5 days of streptozotocin injection followed by 30 min of middle cerebral artery occlusion (MCAO). We found that diabetes enhanced the MCAO-induced elevation of NRSF in the hippocampus in accompany with an elevation of its corepressors, HDAC1, and mSin3A, and decrease of β-TrCP. By using histological/immunofluorescence staining and neurobehavioral testing, our results showed that the brain damage and learning/memory impairment were aggravated in diabetic ischemic mice but significantly attenuated after stereotaxic injection of NRSF-shRNA. Meanwhile, by performing whole-brain clearing with PEGASOS, microvascular reconstruction, western blotting, and ELISA, we found that NRSF-shRNA markedly alleviated the vasculature disorders and rescued the suppression of NRP-1, VEGF, and VEGFR2 in the hippocampus of diabetic ischemic mice. Therefore, our results demonstrated for the first time that the elevation of hippocampal NRSF plays an important role in alleviating brain injury and cognitive disabilities in diabetic ischemic mice, potentially via the reduction of NRP-1/VEGF signaling.
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spelling pubmed-91364172022-05-28 Knockdown of NRSF Alleviates Ischemic Brain Injury and Microvasculature Defects in Diabetic MCAO Mice He, Cheng-Feng Xue, Wen-Jiao Xu, Xiao-Die Wang, Jian-Tao Wang, Xin-Ru Feng, Yi Zhou, Hou-Guang Guo, Jing-Chun Front Neurol Neurology Diabetes is one of the well-established risk factors of stroke and is associated with a poor outcome in patients with stroke. Previous studies have shown that the expression of neuron restrictive silencer factor (NRSF) is elevated in diabetes as well as ischemic stroke. However, the role of NRSF in regulating an outcome of diabetic ischemic stroke has not been completely understood. Here, we hypothesized that diabetes-induced NRSF elevation can aggravate brain injury and cognition impairment in ischemic stroke. The diabetic ischemic stroke mice model was established by 8 weeks of high-fat-diet feeding and 5 days of streptozotocin injection followed by 30 min of middle cerebral artery occlusion (MCAO). We found that diabetes enhanced the MCAO-induced elevation of NRSF in the hippocampus in accompany with an elevation of its corepressors, HDAC1, and mSin3A, and decrease of β-TrCP. By using histological/immunofluorescence staining and neurobehavioral testing, our results showed that the brain damage and learning/memory impairment were aggravated in diabetic ischemic mice but significantly attenuated after stereotaxic injection of NRSF-shRNA. Meanwhile, by performing whole-brain clearing with PEGASOS, microvascular reconstruction, western blotting, and ELISA, we found that NRSF-shRNA markedly alleviated the vasculature disorders and rescued the suppression of NRP-1, VEGF, and VEGFR2 in the hippocampus of diabetic ischemic mice. Therefore, our results demonstrated for the first time that the elevation of hippocampal NRSF plays an important role in alleviating brain injury and cognitive disabilities in diabetic ischemic mice, potentially via the reduction of NRP-1/VEGF signaling. Frontiers Media S.A. 2022-05-13 /pmc/articles/PMC9136417/ /pubmed/35645950 http://dx.doi.org/10.3389/fneur.2022.869220 Text en Copyright © 2022 He, Xue, Xu, Wang, Wang, Feng, Zhou and Guo. https://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 Neurology
He, Cheng-Feng
Xue, Wen-Jiao
Xu, Xiao-Die
Wang, Jian-Tao
Wang, Xin-Ru
Feng, Yi
Zhou, Hou-Guang
Guo, Jing-Chun
Knockdown of NRSF Alleviates Ischemic Brain Injury and Microvasculature Defects in Diabetic MCAO Mice
title Knockdown of NRSF Alleviates Ischemic Brain Injury and Microvasculature Defects in Diabetic MCAO Mice
title_full Knockdown of NRSF Alleviates Ischemic Brain Injury and Microvasculature Defects in Diabetic MCAO Mice
title_fullStr Knockdown of NRSF Alleviates Ischemic Brain Injury and Microvasculature Defects in Diabetic MCAO Mice
title_full_unstemmed Knockdown of NRSF Alleviates Ischemic Brain Injury and Microvasculature Defects in Diabetic MCAO Mice
title_short Knockdown of NRSF Alleviates Ischemic Brain Injury and Microvasculature Defects in Diabetic MCAO Mice
title_sort knockdown of nrsf alleviates ischemic brain injury and microvasculature defects in diabetic mcao mice
topic Neurology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9136417/
https://www.ncbi.nlm.nih.gov/pubmed/35645950
http://dx.doi.org/10.3389/fneur.2022.869220
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