Valproic Acid Reduces Vasospasm through Modulation of Akt Phosphorylation and Attenuates Neuronal Apoptosis in Subarachnoid Hemorrhage Rats

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.

2-PMAP Ameliorates Cerebral Vasospasm and Brain Injury after Subarachnoid Hemorrhage by Regulating Neuro-Inflammation in Rats

“…An SAH can cause apoptosis in the cerebral cortex, with poor prognoses [ 9 , 28 ]. In this work, the protective effect of 2PMAP against neuronal apoptosis was evaluated by performing TUNEL staining 48 h after SAH with neurons marked by NeuN.…”

“…Approximately 10 out of 100,000 people each year experience SAH with residual sequela and economic burdens [ 32 ]. Despite advanced surgical techniques, EBI and vasospasm remain the major causes of mortality and morbidity [ 9 , 33 ]. Vasospasm induces ischemic damage to brain, in which the outcomes depend on the extent of the damage [ 1 ].…”

“…Cell death signals result in not only mitochondrial dysfunction but also caspase pathways, which are downstream of the Bcl-2 family [ 72 ]. Since the pro-survival protein, Bcl-2, regulates the activation or cleavage of caspases, and further suppresses the formation of pro-apoptotic proteins, Bax and Bad, the ratio of Bcl-2 to Bax usually indicates whether cell survival or cell death is the most dominate event [ 9 ]. In our study, SAH not only induced the increased production of ROS and cleaved caspase-3 in the brain tissues of the rats but also decreased the ratio of Bcl-2 to Bax; the administration of 2-PMAP improved these expressions.…”

“…The intima-media thickness was measured as the maximal distance between the internal intima and the outer adventitia. The ratio of the cross-sectional area to the intima-media thickness was analyzed to assess the severity of vasospasm based on previous studies from the literature [ 9 , 25 , 26 , 27 ].…”

“…Notably, one study has demonstrated that, after SAH, apoptosis participates in aneurysm formation, vasospasm and EBI [ 8 ]. After global ischemia, patients with SAH exhibit apoptosis in the vasculature, blood–brain barrier (BBB) and brain [ 9 ]. Mechanisms of secondary brain injury after SAH are multifactorial.…”