机构：[1]Department of Neurology, The Second Affiliated Hospital of Soochow University, Suzhou City, China[2]The Institute of Neuroscience, Soochow University, Suzhou City, China[3]Department of Pharmacology, Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee[4]Department of Neurology, Subei People’s Hospital, Yangzhou City, China苏北人民医院[5]Department of Human Anatomy and Cell Science, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada
Connexin43 (Cx43) is one of the most abundant gap junction proteins in the central nervous system. Abnormal opening of Cx43 hemichannels after ischemic insults causes apoptotic cell death. In this study, we found persistently increased expression of Cx43 8 h to 7 d after hypoxia/ischemia (HI) injury in neonatal rats. Pre-treatment with Gap26 and Gap27, two Cx43 mimetic peptides, significantly reduced cerebral infarct volume. Gap26 treatment at 24 h after ischemia improved functional recovery on muscle strength, motor coordination, and spatial memory abilities. Further, Gap26 inhibited Cx43 expression and reduced active astrogliosis. Gap26 interacted and co-localized with Cx43 together in brain tissues and cultured astrocytes. After oxygen glucose deprivation, Gap26 treatment reduced the total Cx43 level in cultured astrocytes; but Cx43 level in the plasma membrane was increased. Degradation of Cx43 in the cytoplasm was mainly via the ubiquitin proteasome pathway. Concurrently, phosphorylated Akt, which phosphorylates Cx43 on Serine(373) and facilitates the forward transport of Cx43 to the plasma membrane, was increased by Gap26 treatment. Microdialysis showed that increased membranous Cx43 causes glutamate release by opening Cx43 hemichannels. Extracellular glutamate concentration was significantly decreased by Gap26 treatment in vivo. Finally, we found that cleaved caspase-3, an apoptosis marker, was attenuated after HI injury by Gap26 treatment. Effects of Gap27 were analogous to those of Gap26. In summary, our findings demonstrate that modulation of Cx43 expression and astroglial function is a potential therapeutic strategy for ischemic brain injury. GLIA 2015;63:1553-1567
基金：
Grant sponsor: National Natural Science Foundation of China;
Grant number: 81071095, 81120108011, 81361128010, and
81400963; Grant sponsor: Canadian Institutes of Health
Research (CIHR); Grant number: CCI-132567; Grant
sponsor: Priority Academic Program Development of Jiangsu
Higher Education Institutions of China.
第一作者机构：[1]Department of Neurology, The Second Affiliated Hospital of Soochow University, Suzhou City, China[2]The Institute of Neuroscience, Soochow University, Suzhou City, China
共同第一作者：
通讯作者：
通讯机构：[1]Department of Neurology, The Second Affiliated Hospital of Soochow University, Suzhou City, China
推荐引用方式(GB/T 7714)：
Xiaojing Li,Heqing Zhao,Xianxing Tan,et al.Inhibition of connexin43 improves functional recovery after ischemic brain injury in neonatal rats[J].GLIA.2015,63(9):1553-67.doi:10.1002/glia.22826.
APA：
Xiaojing Li,Heqing Zhao,Xianxing Tan,Richard M. Kostrzewa,Gang Du...&Xingshun Xu.(2015).Inhibition of connexin43 improves functional recovery after ischemic brain injury in neonatal rats.GLIA,63,(9)
MLA：
Xiaojing Li,et al."Inhibition of connexin43 improves functional recovery after ischemic brain injury in neonatal rats".GLIA 63..9(2015):1553-67
