title: Inhibition of connexin43 improves functional recovery after ischemic brain injury in neonatal rats.
abstract: 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.
authors.affiliation: Department of Neurology, The Second Affiliated Hospital of Soochow University, Suzhou City, China.|The Institute of Neuroscience, Soochow University, Suzhou City, China.
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Neurology, The Second Affiliated Hospital of Soochow University, Suzhou City, China.
authors.forename: Heqing
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Department of Neurology, The Second Affiliated Hospital of Soochow University, Suzhou City, China.|The Institute of Neuroscience, Soochow University, Suzhou City, China.
authors.forename: Xianxing
authors.initials: X
authors.lastname: Tan
authors.affiliation: Department of Pharmacology, Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Kostrzewa
authors.affiliation: Department of Neurology, The Second Affiliated Hospital of Soochow University, Suzhou City, China.|The Institute of Neuroscience, Soochow University, Suzhou City, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Du
authors.affiliation: Department of Neurology, The Second Affiliated Hospital of Soochow University, Suzhou City, China.|The Institute of Neuroscience, Soochow University, Suzhou City, China.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Neurology, The Second Affiliated Hospital of Soochow University, Suzhou City, China.
authors.forename: Jiangtao
authors.initials: J
authors.lastname: Zhu
authors.affiliation: The Institute of Neuroscience, Soochow University, Suzhou City, China.
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Miao
authors.affiliation: Department of Neurology, Subei People's Hospital, Yangzhou City, China.
authors.forename: Hailong
authors.initials: H
authors.lastname: Yu
authors.affiliation: Department of Human Anatomy and Cell Science, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: Jiming
authors.initials: J
authors.lastname: Kong
authors.affiliation: Department of Neurology, The Second Affiliated Hospital of Soochow University, Suzhou City, China.|The Institute of Neuroscience, Soochow University, Suzhou City, China.
authors.forename: Xingshun
authors.initials: X
authors.lastname: Xu
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002545:Brain Ischemia / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology / Q000523:psychology; D015687:Cell Hypoxia / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D018031:Connexin 43 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017630:Connexins / Q000494:pharmacology*; D004195:Disease Models, Animal; D005911:Gliosis / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology / Q000523:psychology; D005947:Glucose / Q000172:deficiency; D018698:Glutamic Acid / Q000378:metabolism; D000860:Hypoxia / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology / Q000523:psychology; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D053580:Muscle Strength / Q000187:drug effects / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009842:Oligopeptides; D010455:Peptides / Q000494:pharmacology*; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function / Q000187:drug effects* / Q000502:physiology; D065852:Spatial Memory / Q000187:drug effects / Q000502:physiology
chemical_list: D018031:Connexin 43; D017630:Connexins; C514423:Gap 26 peptide; C580592:Gja1 protein, rat; D018696:Neuroprotective Agents; D009842:Oligopeptides; D010455:Peptides; C455880:gap 27 peptide; D018698:Glutamic Acid; D005947:Glucose
keywords: astrocyte; caspase-3; connexin43; glutamate; ischemic brain injury