title: Mammalian target of rapamycin (mTOR) inhibition reduces cerebral vasospasm following a subarachnoid hemorrhage injury in canines.
abstract: Mammalian target of rapamycin (mTOR) pathway is a serine/threonine protein kinase that plays a vital role in regulating growth, proliferation, survival, and protein synthesis among cells. In the present study, we investigated the role of the mTOR pathway following subarachnoid hemorrhage brain injury--specifically investigating its ability to mediate the activation of cerebral vasospasm. Additionally, we investigated whether key signaling pathway molecules such as the mTOR, P70S6K1, and 4E-BP1 play a role in the process. Thirty dogs were randomly divided into 5 groups: sham, SAH (subarachnoid hemorrhage), SAH+DMSO (dimethyl sulfoxide), SAH+Rapamycin and SAH+AZD8055. An established canine double-hemorrhage model of SAH was used by injecting autologous arterial blood into the cisterna magna on days 0 and 2. Angiography was performed at days 0 and 7. Clinical behavior, histology, immunohistochemistry, and Western blot of mTOR, P70S6K1, 4E-BP1 and PCNA (proliferating cell nuclear antigen) in the basilar arteries were examined. In the SAH and SAH+DMSO groups, severe angiographic vasospasm was obtained (34.3±19.8%, 38.4±10.3) compared with that in Sham (93.9±5.0%) respectively. mTOR, P70S6K1, 4E-BP1 and PCNA increased in the sample of spastic basilar arteries (p<0.05). In the SAH+RAPA and SAH+AZD8055 groups, Rapamycin and AZD8055 attenuated angiographic vasospasm (62.3±15.9% and 65.2±10.3%) while improving appetite and activity scores (p<0.05) on days 5 through 7. Rapamycin and AZD8055 significantly reduced the level and expression of mTOR, P70S6K1, 4E-BP1 and PCNA (p<0.05). In conclusion, our study suggests that the mTOR molecular signaling pathway plays a significant role in cerebral vasospasm following SAH, and that inhibition of the mTOR pathway has the potential to become an attractive strategy to treat vasospasm following SAH.
authors.affiliation: Department of Anatomy, Shandong University School of Medicine, Shandong 250012, China.
authors.forename: Weiguang
authors.initials: W
authors.lastname: Zhang
authors.forename: Nikan H
authors.initials: NH
authors.lastname: Khatibi
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Yamaguchi-Okada
authors.forename: Junhao
authors.initials: J
authors.lastname: Yan
authors.forename: Chunhua
authors.initials: C
authors.lastname: Chen
authors.forename: Qin
authors.initials: Q
authors.lastname: Hu
authors.forename: Haiwei
authors.initials: H
authors.lastname: Meng
authors.forename: Hongbin
authors.initials: H
authors.lastname: Han
authors.forename: Shuwei
authors.initials: S
authors.lastname: Liu
authors.forename: Changman
authors.initials: C
authors.lastname: Zhou
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D004285:Dogs; D005260:Female; D008297:Male; D009025:Morpholines / Q000494:pharmacology / Q000627:therapeutic use; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology / Q000627:therapeutic use; D013345:Subarachnoid Hemorrhage / Q000150:complications / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D020301:Vasospasm, Intracranial / Q000209:etiology / Q000378:metabolism* / Q000517:prevention & control*
chemical_list: D009025:Morpholines; C546624:(5-(2,4-bis((3S)-3-methylmorpholin-4-yl)pyrido(2,3-d)pyrimidin-7-yl)-2-methoxyphenyl)methanol; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus