Gamma-secretase inhibitor (GSI1) attenuates morphological cerebral vasospasm in 24h after experimental subarachnoid hemorrhage in rats.
Notch signaling plays an important role in the arteriogenesis. We hypothesized that the Notch inhibitor--gamma-secretase inhibitor (GSI1) exerted its effects on the vasospasm via regulation of NF-kappaB and MMP-9. In this study, 160 male Sprague-Dawley (SD) rats were randomly assigned into four groups: Sham, subarachnoid hemorrhage (SAH), SAH treated with dimethyl sulfoxide (DMSO) and SAH treated with GSI1. After 24h SAH, the mortality, neurological scores, blood-brain barrier permeability and brain water content were examined. The mRNA and protein level of Notch1, the expression and activity of NF-kappaB and MMP-9 were evaluated. Severe morphological vasospasm in the basilar artery was observed in SAH and DMSO treated rats. GSI1 significantly effected on neurological deficits, but not on mortality; significantly reduced morphological vasospasm, blood-brain barrier permeability, brain water content; significantly decreased the protein level of Notch1, NF-kappaB p50 and MMP-9, as well as the DNA-binding activity of NF-kappaB (EMSA) and the activity of MMP-9 (Zymography). These findings suggest that GSI1 plays a critical role in the attenuation of acute cerebral vasospasm, which may provide a novel therapeutic target for cerebral vasospasm after SAH insult.
Yang
Xiaomei
X
Department of Anatomy and Embryology, Peking University Health Science Center, 38 Xueyuan Rd, Hai Dian Qu, Beijing, 100191, China.
Chen
Chunhua
C
Hu
Qin
Q
Yan
Junhao
J
Zhou
Changman
C
D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008297:Male; D018696:Neuroprotective Agents / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D051881:Receptor, Notch1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012997:Solvents / Q000494:pharmacology; D013345:Subarachnoid Hemorrhage / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D013997:Time Factors; D016896:Treatment Outcome; D020301:Vasospasm, Intracranial / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
D004791:Enzyme Inhibitors; D018696:Neuroprotective Agents; C497763:Notch1 protein, rat; D012333:RNA, Messenger; D051881:Receptor, Notch1; D012997:Solvents; D053829:Amyloid Precursor Protein Secretases; D004121:Dimethyl Sulfoxide