title: Sestrin2, as a negative feedback regulator of mTOR, provides neuroprotection by activation AMPK phosphorylation in neonatal hypoxic-ischemic encephalopathy in rat pups.
abstract: Hypoxic-ischemic encephalopathy is a condition caused by reduced oxygen and cerebral blood flow to the brain resulting in neurological impairments. Effective therapeutic treatments to ameliorate these disabilities are still lacking. We sought to investigate the role of sestrin2, a highly conserved stress-inducible protein, in a neonatal rat hypoxic-ischemic encephalopathy model. Ten-day-old rat pups underwent right common carotid artery ligation followed by 2.5 h hypoxia. At 1 h post hypoxic-ischemic encephalopathy, rats were intranasally administered with recombinant human sestrin2 and sacrificed for brain infarct area measurement, Fluoro-Jade C, immunofluorescence staining, Western blot, and neurological function testing. rh-sestrin2 reduced brain infarct area, brain atrophy, apoptosis, ventricular area enlargement, and improved neurological function. Western blot showed that sestrin2 expression levels were increased after treatment with rh-sestrin2, and sestrin2 exerts neuroprotective effects via activation of the adenosine monophosphate-activated protein kinase pathway which in turn inhibits mammalian target of rapamycin signaling resulting in the attenuation of apoptosis. In conclusions: Sestrin2 plays an important neuroprotective role after hypoxic-ischemic encephalopathy via adenosine monophosphate-activated protein kinase signaling pathway and serves as a negative feedback regulator of mammalian target of rapamycin. Administration of rh-sestrin2 not only reduced infarct area and brain atrophy, but also significantly improved neurological function.
authors.affiliation: 1 Department of Anesthesiology, School of Medicine, The Second Affiliated Hospital, Zhejiang University, Hangzhou, Zhejiang, China.|2 Departments of Anesthesiology and Basic Sciences, School of Medicine, Loma Linda University, Loma Linda, CA, USA.
authors.forename: Xudan
authors.initials: X
authors.lastname: Shi
authors.affiliation: 2 Departments of Anesthesiology and Basic Sciences, School of Medicine, Loma Linda University, Loma Linda, CA, USA.
authors.forename: Liang
authors.initials: L
authors.lastname: Xu
authors.affiliation: 2 Departments of Anesthesiology and Basic Sciences, School of Medicine, Loma Linda University, Loma Linda, CA, USA.
authors.forename: Desislava Met
authors.initials: DM
authors.lastname: Doycheva
authors.affiliation: 2 Departments of Anesthesiology and Basic Sciences, School of Medicine, Loma Linda University, Loma Linda, CA, USA.
authors.forename: Jiping
authors.initials: J
authors.lastname: Tang
authors.affiliation: 1 Department of Anesthesiology, School of Medicine, The Second Affiliated Hospital, Zhejiang University, Hangzhou, Zhejiang, China.
authors.forename: Min
authors.initials: M
authors.lastname: Yan
authors.affiliation: 2 Departments of Anesthesiology and Basic Sciences, School of Medicine, Loma Linda University, Loma Linda, CA, USA.
authors.forename: John H
authors.initials: JH
authors.lastname: Zhang
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D001522:Behavior, Animal / Q000187:drug effects; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D025461:Feedback, Physiological / Q000502:physiology*; D020925:Hypoxia-Ischemia, Brain / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000627:therapeutic use; D009687:Nuclear Proteins / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism* / Q000627:therapeutic use; D010766:Phosphorylation; D034741:RNA, Small Interfering / Q000235:genetics; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000627:therapeutic use; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D000084622:Sestrins
chemical_list: D055372:AMP-Activated Protein Kinases; D018696:Neuroprotective Agents; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; D058570:TOR Serine-Threonine Kinases; C465398:SESN2 protein, human; D000084622:Sestrins; C583887:Sesn2 protein, rat; C546845:mTOR protein, rat
keywords: Sestrins; adenosine monophosphate-activated protein kinase; apoptosis; mammalian target of rapamycin; neonatal hypoxic-ischemic encephalopathy