Abstract
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.
Highlights
Aneurysmal subarachnoid hemorrhage (SAH) occurs in a minority of strokes [1,2] but is a devastating neurologic event associated with mortality and morbidity rates exceeding 50% [3,4]
To measure the effect of VPA in SAH rats, they were divided into five groups: sham 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)
In comparison with the sham group, the mean cross-sectional areas of basilar arteries (BA) were significantly lower in the SAH group (26% lower; p < 0.01), in the SAH-VPA10 group (26% lower; p < 0.01), and in the SAH-VPA20 group (20% lower; p < 0.05)
Summary
Aneurysmal subarachnoid hemorrhage (SAH) occurs in a minority of strokes [1,2] but is a devastating neurologic event associated with mortality and morbidity rates exceeding 50% [3,4]. It affects relatively young patients, and one-third of survivors are rendered dependent due to major disability requiring costly medical care [2]. Other preclinical studies have demonstrated neuro-protective properties in rat models of ischemic stroke [27,28] and neurodegenerative disease [29,30] Their association with VPA in cerebral vasospasm has not been fully illustrated. This study used a rat model of SAH to investigate whether VPA attenuates cerebral vasospasm or exerts a neuroprotective effect
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