PMID- 22177999
OWN - NLM
STAT- MEDLINE
DCOM- 20120326
LR  - 20211203
IS  - 1090-2430 (Electronic)
IS  - 0014-4886 (Linking)
VI  - 233
IP  - 2
DP  - 2012 Feb
TI  - Mammalian target of rapamycin (mTOR) inhibition reduces cerebral vasospasm 
      following a subarachnoid hemorrhage injury in canines.
PG  - 799-806
LID - 10.1016/j.expneurol.2011.11.046 [doi]
AB  - 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.
CI  - Copyright (c) 2011 Elsevier Inc. All rights reserved.
FAU - Zhang, Weiguang
AU  - Zhang W
AD  - Department of Anatomy, Shandong University School of Medicine, Shandong 250012, 
      China.
FAU - Khatibi, Nikan H
AU  - Khatibi NH
FAU - Yamaguchi-Okada, Mitsuo
AU  - Yamaguchi-Okada M
FAU - Yan, Junhao
AU  - Yan J
FAU - Chen, Chunhua
AU  - Chen C
FAU - Hu, Qin
AU  - Hu Q
FAU - Meng, Haiwei
AU  - Meng H
FAU - Han, Hongbin
AU  - Han H
FAU - Liu, Shuwei
AU  - Liu S
FAU - Zhou, Changman
AU  - Zhou C
LA  - eng
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20111208
PL  - United States
TA  - Exp Neurol
JT  - Experimental neurology
JID - 0370712
RN  - 0 (Morpholines)
RN  - 970JJ37FPW 
      ((5-(2,4-bis((3S)-3-methylmorpholin-4-yl)pyrido(2,3-d)pyrimidin-7-yl)-2-methoxyphenyl)methanol)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Animals
MH  - Cell Proliferation/drug effects
MH  - Dogs
MH  - Female
MH  - Male
MH  - Morpholines/pharmacology/therapeutic use
MH  - Muscle, Smooth, Vascular/drug effects/metabolism
MH  - Sirolimus/pharmacology/therapeutic use
MH  - Subarachnoid Hemorrhage/complications/*metabolism
MH  - TOR Serine-Threonine Kinases/*antagonists & inhibitors/*biosynthesis
MH  - Vasospasm, Intracranial/etiology/*metabolism/*prevention & control
EDAT- 2011/12/20 06:00
MHDA- 2012/03/27 06:00
CRDT- 2011/12/20 06:00
PHST- 2011/09/01 00:00 [received]
PHST- 2011/11/17 00:00 [revised]
PHST- 2011/11/29 00:00 [accepted]
PHST- 2011/12/20 06:00 [entrez]
PHST- 2011/12/20 06:00 [pubmed]
PHST- 2012/03/27 06:00 [medline]
AID - S0014-4886(11)00450-X [pii]
AID - 10.1016/j.expneurol.2011.11.046 [doi]
PST - ppublish
SO  - Exp Neurol. 2012 Feb;233(2):799-806. doi: 10.1016/j.expneurol.2011.11.046. Epub 
      2011 Dec 8.