Effect of valproic acid on survival and neurologic outcomes in an asphyxial cardiac arrest model of rats

Abstract

Aim of the study: Valproic acid (VPA) has been known to reduce neuronal injury, has anti-inflammatory and anti-apoptotic effects as a histone deacetylase (HDAC) inhibitor. Thus, this study was performed to investigate the effects of VPA on survival and neurological outcomes in an asphyxial cardiac arrest model of rats.

Methods: Male Sprague-Dawley rats were subjected to asphyxial cardiac arrest. For survival study, rats were subjected to 450s of asphyxial cardiac arrest. Cardiopulmonary resuscitation (CPR) was performed and then rats were blindly allocated to one of two groups (control group, n=10; VPA group, n=10). Valproic acid (300mgkg(-1)) or vehicle (normal saline) was administered via tail vein immediately after return of spontaneous circulation (ROSC) and observed for 72h. For neurological outcome study, rats (n=7 for each group) were subjected to same experimental procedures except duration of cardiac arrest of 360s. Neurological deficit scale (NDS) score was measured every 24h after ROSC for 72h and was ranged from 0 (brain dead) to 80 (normal). Brain tissues were harvested at 72h for evaluation of apoptotic injury and acetylation status of histone H3.

Results: In survival study, 2 rats in VPA group were excluded because cardiac arrest was not achieved in predetermined time. Thus, 10 rats were allocated to control group and 8 rats were allocated to VPA group. The survival rates at 72h after cardiac arrest were significantly higher in VPA group than in control group (6/8 in VPA group, 3/10 rats in control group; log rank test, p<0.05). In neurological outcome study, all rats survived for 72h and NDS at 72h were significantly higher in VPA group than in control group (p<0.05). In brain tissues, expressions of acetylated histone H3 were not significantly different. However, expressions of cleaved caspase-3 were significantly lower in VPA group than in control group (p<0.05).

Conclusion: VPA increased survival rates and improved neurologic outcome in asphyxial cardiac arrest model of rats while decreasing expressions of cleaved caspase-3.

Keywords: Apoptosis; Cardiac arrest; Histone deacetylase inhibitor; Valproic acid.