A Primary Study Of SIRT1/P53Pathway Which Involves In The Physiopathologic Mechanisms Of Brain Edema After Experimental Subarachnoid Hemorrhage

Backgrounds and Objectives: Aneurismal subarachnoid hemorrhage (SAH), a subtype ofstroke, has particularly high morbidity and mortality. Brain edema is a major cause ofneurological impairment after SAH, and its physiopathologic mechanisms are poorlyunderstood. We utilized a rat model of SAH to investigate whether SIRT1has a protectiverole against brain edema via the tumor suppressor protein p53pathway, which will help thetherapeutic study in future.Methods: Experimental SAH was induced in adult male Sprague-Dawley rats byprechiasmatic cistern injection. In experiment1,36rats were arranged into every group,and brain SIRT1protein levels were examined in the sham-operated controls, and in rats6,12,24,48, and72h by western blotting and immunohistochemistry after SAH induction.In experiment2,132rats were arranged: control (n=30), SAH (n=30), SAH+DMSO(n=30), SAH+sirtinol (L，n=12)、SAH+sirtinol (H，n=30). The SIRT1inhibitor sirtinolwas administered by intracerebroventricular infusion. Neurological functions, blood-brainbarrier (BBB) disruption, and brain water content were assessed. Endothelial cell apoptosis,caspase3protein expression, p53acetylation and matrix metalloproteinase (MMP)-9activity were examined.Results: Compared with the control, SIRT1protein expression increased remarkably,reaching a maximum at24h after SAH （P <0.05）. Sirtinol treatment significantlylowered SIRT1expression （P <0.05）, accompanied by deteriorated neurologic function,BBB disruption, and brain edema, and increased endothelial cell apoptosis and MMP-9gelatinase activity compared to the rats treated with the vehicle only （P <0.05）.Conclusion: Our results suggest that there is an increased expression of endogenousSIRT1after SAH, and this increment may exert a neuroprotective role against brain edemaafter SAH.