title: Inhibition of mammalian target of rapamycin attenuates early brain injury through modulating microglial polarization after experimental subarachnoid hemorrhage in rats.
abstract: Here, we aimed to study the role and underlying mechanism of mTOR in early brain injury (EBI) after subarachnoid hemorrhage (SAH). Experiment 1, the time course of mTOR activation in the cortex following SAH. Experiment 2, the role of mTOR in SAH-induced EBI. Adult SD rats were divided into four groups: sham group (n=18), SAH+vehicle group (n=18), SAH+rapamycin group (n=18), SAH+AZD8055 group (n=18). Experiment 3, we incubated enriched microglia with OxyHb. Rapamycin and AZD8055 were also used to demonstrate the mTOR's role on microglial polarization in vitro. The phosphorylation levels of mTOR and its substrates were significantly increased and peaked at 24h after SAH. Rapamycin or AZD8055 markedly decreased the phosphorylation levels of mTOR and its substrates and the activation of microglia in vivo, and promoted the microglial polarization from M1 phenotype to M2 phenotype. In addition, administration of rapamycin and AZD8055 following SAH significantly ameliorated EBI, including neuronal apoptosis, neuronal necrosis, brain edema and blood-brain barrier permeability. Our findings suggested that the rapamycin and AZD8055 could attenuate the development of EBI in this SAH model, possibly through inhibiting the activation of microglia by mTOR pathway.
authors.affiliation: Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou 215006, China.
authors.forename: Wanchun
authors.initials: W
authors.lastname: You
authors.affiliation: Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou 215006, China.
authors.forename: Zhong
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou 215006, China.
authors.forename: Haiying
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou 215006, China.
authors.forename: Haitao
authors.initials: H
authors.lastname: Shen
authors.affiliation: Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou 215006, China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Xu
authors.affiliation: Department of Neurosurgery, The People's Hospital of Rugao, Jiangsu, Rugao 226500, China.
authors.forename: Genlai
authors.initials: G
authors.lastname: Jia
authors.affiliation: Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou 215006, China. Electronic address: sz_neurosurgery@163.com.
authors.forename: Gang
authors.initials: G
authors.lastname: Chen
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001929:Brain Edema / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D002199:Capillary Permeability / Q000187:drug effects / Q000502:physiology; D016764:Cell Polarity / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology*; D009336:Necrosis / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D011897:Random Allocation; D017207:Rats, Sprague-Dawley; D020123:Sirolimus / Q000494:pharmacology*; D013345:Subarachnoid Hemorrhage / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D009025:Morpholines; D018696:Neuroprotective Agents; C546624:(5-(2,4-bis((3S)-3-methylmorpholin-4-yl)pyrido(2,3-d)pyrimidin-7-yl)-2-methoxyphenyl)methanol; C546845:mTOR protein, rat; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
keywords: Early brain injury; Inflammation; Mammalian target of rapamycin; Microglia polarization; Subarachnoid hemorrhage