SIRT1 inhibition by sirtinol aggravates brain edema after experimental subarachnoid hemorrhage.
Secondary brain injury following subarachnoid hemorrhage (SAH) is poorly understood. We utilized a rat model of SAH to investigate whether SIRT1 has a protective role against brain edema via the tumor suppressor protein p53 pathway. Experimental SAH was induced in adult male Sprague-Dawley rats by prechiasmatic cistern injection. Brain SIRT1 protein levels were examined in the sham controls and in rats 6, 12, 24, 48, and 72 hr after SAH induction. The SIRT1 inhibitor sirtinol was administered by intracerebroventricular infusion. Neurological functions, blood-brain barrier (BBB) disruption, and brain water content were assessed. Endothelial cell apoptosis, caspase 3 protein expression, p53 acetylation, and matrix metalloproteinase-9 (MMP-9) activity were examined. Compared with the control, SIRT1 protein expression increased remarkably, reaching a maximum at 24 hr after SAH. Sirtinol treatment significantly lowered SIRT1 expression, accompanied by deteriorated neurologic function, BBB disruption, brain edema, increased endothelial cell apoptosis, and increased MMP-9 gelatinase activity compared with the rats treated with vehicle only. Our results suggest that increased expression of endogenous SIRT1 may play a neuroprotective role against brain edema after SAH.
Department of Neurosurgery, Jinling Hospital, School of Medicine, Second Military Medical University, Shanghai, China.
Xiao-Ming
XM
Zhou
Xin
X
Zhang
Xiang-Sheng
XS
Zhang
Zong
Z
Zhuang
Wei
W
Li
Qing
Q
Sun
Tao
T
Li
Chun-Xi
CX
Wang
Lin
L
Zhu
Ji-Xin
JX
Shi
Meng-Liang
ML
Zhou
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides / Q000494:pharmacology; D001812:Blood-Brain Barrier / Q000187:drug effects; D001929:Brain Edema / Q000209:etiology / Q000378:metabolism*; D002199:Capillary Permeability / Q000187:drug effects; D004195:Disease Models, Animal; D007150:Immunohistochemistry; D008297:Male; D009284:Naphthols / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D056564:Sirtuin 1 / Q000378:metabolism*; D013345:Subarachnoid Hemorrhage / Q000150:complications* / Q000378:metabolism*
D001549:Benzamides; D009284:Naphthols; C439060:sirtinol; C488368:Sirt1 protein, rat; D056564:Sirtuin 1
MMP-9; SIRT1; cerebral microvasculature; early brain injury; edema; p53; subarachnoid hemorrhage