title: Inhibition of mTOR Pathway by Rapamycin Reduces Brain Damage in Rats Subjected to Transient Forebrain Ischemia.
abstract: The aims of this study are to clarify the role of mTOR in mediating cerebral ischemic brain damage and the effects of rapamycin on ischemic outcomes. Ten minutes of forebrain ischemia was induced in rats, and their brains were sampled after 3 h, 16 h, and 7 days reperfusion for histology, immunohistochemistry and biochemical analysis. Our data demonstrated that cerebral ischemia resulted in both apoptotic and necrotic neuronal death; cerebral ischemia and reperfusion led to significant increases of mRNA and protein levels of p-mTOR and its downstream p-P70S6K and p-S6; elevation of LC3-II, and release of cytochrome c into the cytoplasm in both the cortex and hippocampus. Inhibition of mTOR by rapamycin markedly reduced ischemia-induced damage; suppressed p-Akt, p-mTOR, p-P70S6K and p-S6 protein levels; decreased LC3-II and Beclin-1; and prevented cytochrome c release in the two structures. All together, these data provide evidence that cerebral ischemia activates mTOR and autophagy pathways. Inhibition of mTOR deactivates the mTOR pathway, suppresses autophagy, prevents cytochrome c release and reduces ischemic brain damage.
authors.affiliation: 1. Neuroscience Center, General Hospital of Ningxia Medical University, Key Laboratory of Craniocerebral Diseases of Ningxia Hui Autonomous Region, Yinchuan 75004, China ; 2. Department of Pharmaceutical Sciences, Biomanufacturing Research Institute Biotechnology Enterprise (BRITE), North Carolina Central University, 1801 Fayetteville Street, Durham, NC 27707, USA.
authors.forename: Xiao
authors.initials: X
authors.lastname: Yang
authors.affiliation: 2. Department of Pharmaceutical Sciences, Biomanufacturing Research Institute Biotechnology Enterprise (BRITE), North Carolina Central University, 1801 Fayetteville Street, Durham, NC 27707, USA ; 3. Department of Human Anatomy, Histology and Embryology, Ningxia Medical University, Yinchuan 75004, China.
authors.forename: Changhun
authors.initials: C
authors.lastname: Hei
authors.affiliation: 2. Department of Pharmaceutical Sciences, Biomanufacturing Research Institute Biotechnology Enterprise (BRITE), North Carolina Central University, 1801 Fayetteville Street, Durham, NC 27707, USA ; 4. Department of Endocrinology, General Hospital of Ningxia Medical University, Yinchuan 750004, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Liu
authors.affiliation: 1. Neuroscience Center, General Hospital of Ningxia Medical University, Key Laboratory of Craniocerebral Diseases of Ningxia Hui Autonomous Region, Yinchuan 75004, China.
authors.forename: Yaozu
authors.initials: Y
authors.lastname: Song
authors.affiliation: 2. Department of Pharmaceutical Sciences, Biomanufacturing Research Institute Biotechnology Enterprise (BRITE), North Carolina Central University, 1801 Fayetteville Street, Durham, NC 27707, USA.
authors.forename: Taylor
authors.initials: T
authors.lastname: Thomas
authors.affiliation: 2. Department of Pharmaceutical Sciences, Biomanufacturing Research Institute Biotechnology Enterprise (BRITE), North Carolina Central University, 1801 Fayetteville Street, Durham, NC 27707, USA.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Tshimanga
authors.affiliation: 1. Neuroscience Center, General Hospital of Ningxia Medical University, Key Laboratory of Craniocerebral Diseases of Ningxia Hui Autonomous Region, Yinchuan 75004, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Wang
authors.affiliation: 1. Neuroscience Center, General Hospital of Ningxia Medical University, Key Laboratory of Craniocerebral Diseases of Ningxia Hui Autonomous Region, Yinchuan 75004, China.
authors.forename: Jianguo
authors.initials: J
authors.lastname: Niu
authors.affiliation: 1. Neuroscience Center, General Hospital of Ningxia Medical University, Key Laboratory of Craniocerebral Diseases of Ningxia Hui Autonomous Region, Yinchuan 75004, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Sun
authors.affiliation: 2. Department of Pharmaceutical Sciences, Biomanufacturing Research Institute Biotechnology Enterprise (BRITE), North Carolina Central University, 1801 Fayetteville Street, Durham, NC 27707, USA.
authors.forename: P Andy
authors.initials: PA
authors.lastname: Li
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000378:metabolism*; D045304:Cytochromes c / Q000378:metabolism; D020287:In Situ Nick-End Labeling; D016548:Prosencephalon / Q000098:blood supply*; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: D012333:RNA, Messenger; D045304:Cytochromes c; C546845:mTOR protein, rat; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
keywords: Autophagy; Cerebral ischemia; Cytochrome c; Rapamycin; Reperfusion damage; mTOR