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. © 2011 Elsevier Inc.