title: Inhibition of mTOR pathway restrains astrocyte proliferation, migration and production of inflammatory mediators after oxygen-glucose deprivation and reoxygenation.
abstract: Glial scar is a major impediment to axonal regeneration in central nervous system (CNS) disorders. Overcoming this physical and biochemical barrier might be crucial for axonal regeneration and functional compensation during the progression of CNS disorders. The mammalian target of rapamycin (mTOR) is an evolutionarily conserved serine/threonine kinase, involved in process of cell proliferation, migration, autophagy and protein synthesis. Rapamycin, an inhibitor of mTOR signaling, can exert neuroprotective effects in several CNS diseases. However, its role in the process of reactive astrogliosis including cell proliferation, migration and cytokine production after cerebral ischemia still remains largely unknown. In this study, we investigated the effects of mTOR blockade in cultured astrocytes exposed to oxygen-glucose deprivation/reoxygenation (OGD/R), a wildly used cellular ischemia model which mimics ideally cerebral ischemia model in vivo. We found that astrocytes became activated after OGD/R, characterized by change of astrocytic morphology, upregulation of GFAP expression, the increase number of Edu positive cells, and accompanied with phosphorylation of mTOR protein and its substrate S6K1. Rapamycin significantly inhibited mTOR signal pathway, suppressed proliferation of astrocytes via modulation of cell cycle progression. Moreover, rapamycin attenuated astrocytic migration and mitigated production of inflammatory factors such as TNF-α and iNOS induced by astrocytes exposed to OGD/R. Taken together, our findings indicated that mTOR blockade by rapamycin attenuates astrocyte migration, proliferation and production of inflammation mediators. We suggest that targeting mTOR pathway in astrocyte activation may represent a potentially new therapeutic strategy against deleterious neurotoxic processes of reactive astrogliosis in CNS disorders such as ischemic stroke.
authors.affiliation: Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China.
authors.forename: Chun-Yu
authors.initials: CY
authors.lastname: Li
authors.affiliation: Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China.
authors.forename: Shuang-Feng
authors.initials: SF
authors.lastname: Liu
authors.affiliation: Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China.
authors.forename: Wen-Sheng
authors.initials: WS
authors.lastname: Qu
authors.affiliation: Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China. Electronic address: tiands@tjh.tjmu.edu.cn.
authors.forename: Dai-Shi
authors.initials: DS
authors.lastname: Tian
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000166:cytology*; D001343:Autophagy / Q000187:drug effects; D002545:Brain Ischemia / Q000188:drug therapy / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects* / Q000502:physiology; D002465:Cell Movement / Q000187:drug effects*; D002478:Cells, Cultured; D005947:Glucose / Q000378:metabolism*; D051379:Mice; D018696:Neuroprotective Agents / Q000494:pharmacology; D010100:Oxygen / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D018696:Neuroprotective Agents; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D005947:Glucose; D010100:Oxygen; D020123:Sirolimus
keywords: Inflammation mediator; Mammalian target of rapamycin; Migration; Oxygen–glucose deprivation; Proliferation; Reactive astrogliosis