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Shrm4 contributes to autophagy inhibition and neuroprotection following ischemic stroke by mediating GABAB receptor activation.

Authors
  • Yuan, Ya-Jing1
  • Ye, Zhi2
  • Yu, Hao3
  • Chen, Yang3
  • Wang, Yu-Wen4
  • Zhao, Jun-Hua4
  • Sun, Ji-Feng4
  • Xu, Li-Ming4, 5
  • 1 Department of Anesthesia, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, P.R. China. , (China)
  • 2 Department of Anesthesia, The Affiliated Xiangya Hospital of Center South University, Changsha, P.R. China. , (China)
  • 3 Department of Radiotherapy, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, P.R. China. , (China)
  • 4 Department of Radiotherapy, Tianjin Medical University Cancer Hospital Airport Hospital, Tianjin, P.R. China. , (China)
  • 5 Department of Radiotherapy, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Tianjin, P.R. China. , (China)
Type
Published Article
Journal
The FASEB Journal
Publisher
Federation of American Society for Experimental Biology
Publication Date
Dec 01, 2020
Volume
34
Issue
12
Pages
15837–15848
Identifiers
DOI: 10.1096/fj.202000458RR
PMID: 33079458
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Acute ischemic stroke is one of the leading causes of death in developed countries and the most common cause of disability in adults worldwide. Despite advances in the understanding of stroke pathophysiology, therapeutic options remain limited. In this study, we explored the interaction of Shrm4 and the metabotropic gamma-aminobutyric acid (GABA) receptors (GABAB ) in ischemic stroke. A transient middle cerebral artery occlusion (MCAO) model was induced by filament insertion in Shrm4+/+ and wild-type C57BL/6J mice, followed by reperfusion for up to 7 days. Baclofen was administered was used to activate GABAB in vivo during reperfusion. Neurological deficits, motor and memory functions, and infarct volume were determined in the various mouse groups. Furthermore, we also developed an oxygen-glucose deprivation (OGD) cell model in primary neurons to test Shrm4/GABAB interactions in vitro. Shrm4 was observed to decrease infarct volume and neuronal cell loss in penumbra, and rescue neurological deficits in MCAO mice. Notably, Shrm4 also increased pole climbing speed, reduced foot faults, and increased escape latency in the Morris water maze test, while reducing neuron autophagy through an interaction with GABAB receptors. GABAB activation using baclofen further reduced OGD-induced neuron damage in culture and stroke outcomes of MCAO, relative to Shrm4 alone. Taken together, Shrm4-mediated GABAB activation confers neuroprotection by reducing neuronal autophagy in acute ischemic stroke. © 2020 Federation of American Societies for Experimental Biology.

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