Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 22, Issue 11, Pages -Publisher
MDPI
DOI: 10.3390/ijms22115975
Keywords
apoptosis; Akt; endothelial nitric oxide synthase (eNOs); ERK; subarachnoid hemorrhage (SAH); valproic acid (VPA); vasospasm
Funding
- Taiwan Ministry of Science and Technology [MOST103-2314-B-037-044-MY2]
- Kaohsiung Medical University Hospital [KMUH 103-3R17]
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In this study, treatment with valproic acid was found to reduce the incidence of delayed cerebral vasospasm induced by aneurysmal subarachnoid hemorrhage in male Sprague-Dawley rats. The improvement in protein expression levels appeared to reverse neuro-apoptosis, indicating a potential anti-vasospastic and neuro-protective effect of VPA through enhanced Akt and/or ERK phosphorylation.
Aneurysmal subarachnoid hemorrhage (SAH) is a devastating emergent event associated with high mortality and morbidity. Survivors usually experience functional neurological sequelae caused by vasospasm-related delayed ischemia. In this study, male Sprague-Dawley rats were randomly assigned to five groups: sham (non-SAH) group, SAH group, and three groups with SAH treated with different doses of valproic acid (VPA) (10, 20, 40 mg/kg, once-daily, for 7 days). The severity of vasospasm was determined by the ratio of cross-sectional areas to intima-media thickness of the basilar arteries (BA) on the seventh day after SAH. The BA showed decreased expression of phospho-Akt proteins. The dentate gyrus showed increased expression of cleaved caspase-3 and Bax proteins and decreased expression of Bcl-2, phospho-ERK 1/2, phospho-Akt and acetyl-histone H3 proteins. The incidence of SAH-induced vasospasm was significantly lower in the SAH group treated with VPA 40 mg/kg (p < 0.001). Moreover, all groups treated with VPA showed reversal of the above-mentioned protein expression in BA and the dentate gyrus. Treatment with VPA upregulated histone H3 acetylation and conferred anti-vasospastic and neuro-protective effects by enhancing Akt and/or ERK phosphorylation. This study demonstrated that VPA could alleviate delayed cerebral vasospasm induced neuro-apoptosis after SAH.
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