The Role Of Mammalian Target Of Rapamycin On Early Brain Injury After Experimental Subarachnoid Hemorrhage And Its Mechanism Research

Background: Mammalian target of rapamycin(m TOR) is an evolutionarily highly conserved serine/threonine kinase, which plays an vital role in autophagy, protein synthesis, lipid synthesis, actin dynamics and neuronal morphology. Previous studies have demonstrated the role of m TOR pathway against brain injury is controversial. However, the role and underlying mechanism of m TOR in modulating microglial viability on early brain injury(EBI) after experiment subarachnoid hemorrhage(SAH) remains unexplored. In this study, we first explored the time course of expression of m TOR pathway, and determined whether inhibiting m TOR signaling could affect the outcome on EBI after SAH and its possible underlying mechanism.Methods: In this study, experiment 1 aimed to investigate the time-course of the m TOR activation in the cortex following SAH. In experiment 2, 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). A rat SAH model was induced by injection of 0.3ml fresh arterial, nonheparinized blood into the prechiasmatic cistern in 20 s, in SAH + rapamycin group, rapamycin was administrated i.p at 150ug/kg at 4h after the induction of SAH, in SAH+ AZD8055 group, AZD8055 was administrated i.p 14mg/kg at 4h after induction of SAH, brain samples were extracted at 24 h after the induction of SAH, which is proved the maximum time point of m TOR activation in experiment 1.Results: Our results demonstrated the protein level of m TOR pathway were significantly increased(p<0.05) and peaked at 24 h. Rapamycin or AZD8055 markedly decreased the expressions of m TOR pathway(p<0.05) and the activation of microglia(p<0.05). In addition, administration of rapamycin and AZD8055 following SAH significantly ameliorated EBI, including neuronal apoptosis, neuronal necrosis, brain edema and blood-brain barrier(BBB) permeability.Conclusions: Our findings suggested that the rapamycin and AZD8055 may essentially attenuate the development of EBI in this SAH model. Possibly through inhibiting the activation of microglia by m TOR pathway.