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.