Neuroserpin alleviates cerebral ischemia-reperfusion injury by suppressing ischemia-induced endoplasmic reticulum stress
Yumei Liao1
Qinghua Zhang2
Qiaoyun Shi2
Peng Liu3
Peiyun Zhong2
Lingling Guo3
Zijian Huang3
Yinghui Peng3
Wei Liu4
Shiqing Zhang3
István Adorján5
Yumi Fukuzaki6
Eri Kawashita7
Xiao-Qi Zhang3
Nan Ma8
Xiaoshen Zhang9
Zoltán Molnár10
Lei Shi1
1.Department of Cardiovascular Surgery,The First Affiliated Hospital,Jinan University,Guangzhou,Guangdong Province,China;State Key Laboratory of Bioactive Molecules and Druggability Assessment,Jinan University,Guangzhou,Guangdong Province,China;JNU-HKUST Joint Laboratory for Neuroscience and Innovative Drug Research;Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research,College of Pharmacy,Jinan University,Guangzhou,Guangdong Province,China2.JNU-HKUST Joint Laboratory for Neuroscience and Innovative Drug Research;Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research,College of Pharmacy,Jinan University,Guangzhou,Guangdong Province,China3.State Key Laboratory of Bioactive Molecules and Druggability Assessment,Jinan University,Guangzhou,Guangdong Province,China;JNU-HKUST Joint Laboratory for Neuroscience and Innovative Drug Research;Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research,College of Pharmacy,Jinan University,Guangzhou,Guangdong Province,China4.Shenzhen Key Laboratory for Neuronal Structural Biology,Biomedical Research Institute;Institute of Geriatric Medicine,Peking University Shenzhen Hospital,Shenzhen Peking University-The Hong Kong University of Science and Technology Medical Center,Shenzhen,Guangdong Province,China5.Department of Anatomy,Histology and Embryology,Semmelweis University,Budapest,Hungary6.Department of Neurology,University of California,San Francisco,San Francisco,CA,USA7.Department of Pathological Biochemistry,Kyoto Pharmaceutical University,Yamashina-ku,Kyoto,Japan8.State Key Laboratory of Bioactive Molecules and Druggability Assessment,Jinan University,Guangzhou,Guangdong Province,China9.Department of Cardiovascular Surgery,The First Affiliated Hospital,Jinan University,Guangzhou,Guangdong Province,China;School of Nursing,Jinan University,Guangzhou,Guangdong Province,China10.Department of Physiology,Anatomy and Genetics,University of Oxford,Oxford,UK
摘要：Neuroserpin,a secreted protein that belongs to the serpin superfamily of serine protease inhibitors,is highly expressed in the central nervous system and plays multiple roles in brain development and pathology.As a natural inhibitor of recombinant tissue plasminogen activator,neuroserpin inhibits the increased activity of tissue plasminogen activator in ischemic conditions and extends the therapeutic windows of tissue plasminogen activator for brain ischemia.However,the neuroprotective mechanism of neuroserpin against ischemic stroke remains unclear.In this study,we used a mouse model of middle cerebral artery occlusion and oxygen-glucose deprivation/reperfusion-injured cortical neurons as in vivo and in vitro ischemia-reperfusion models,respectively.The models were used to investigate the neuroprotective effects of neuroserpin.Our findings revealed that endoplasmic reticulum stress was promptly triggered following ischemia,initially manifesting as the acute activation of endoplasmic reticulum stress transmembrane sensors and the suppression of protein synthesis,which was followed by a later apoptotic response.Notably,ischemic stroke markedly downregulated the expression of neuroserpin in cortical neurons.Exogenous neuroserpin reversed the activation of multiple endoplasmic reticulum stress signaling molecules,the reduction in protein synthesis,and the upregulation of apoptotic transcription factors.This led to a reduction in neuronal death induced by oxygen/glucose deprivation and reperfusion,as well as decreased cerebral infarction and neurological dysfunction in mice with middle cerebral artery occlusion.However,the neuroprotective effects of neuroserpin were markedly inhibited by endoplasmic reticulum stress activators thapsigargin and tunicamycin.Our findings demonstrate that neuroserpin exerts neuroprotective effects on ischemic stroke by suppressing endoplasmic reticulum stress.
机标关键词：neuroserpinischemiastressalleviatescerebralendoplasmicinducedinjury
论文发表日期：2026-01-30
在线出版日期：2025-12-11（本平台首次上网日期，不代表文献的发表时间）
页数：13( 333-345 )
英文信息