Chronic treatment of 4-phenylbutyric acid ameliorates cognitive impairment after focal cerebral ischemia/ reperfusion injury in rats

Abstract

Objectives: Stroke, apart from causing physical disabilities, it also often leads to cognitive impairment in patients. At present, there is no effective drug available for the treatment of post-stroke cognitive impairment. The present study was undertaken to evaluate the ameliorative effect of 4-Phenylbutyric acid (PBA) against cognitive and memory deficits due to focal cerebral ischemia/reperfusion (I/R) in rats. Materials and Methods: Focal cerebral I/R injury was achieved by the middle cerebral artery occlusion (MCAO) method. PBA (100 and 300 mg/kg, i.p.) was administered once daily for 2 weeks. The neurological score was counted to evaluate the severity of neurological motor deficits. The cognitive functions, including learning and memory, were assessed using various paradigms such as Y-maze, passive avoidance task and Morris water maze. Results: The chronic treatment of PBA (100 and 300 mg/kg, i.p.) dose-dependently improved the neurological motor deficits as shown by significant decrease in neurological score in MCAO-treated rats. Besides, PBA (100 and 300 mg/kg, i.p.) treatment markedly improved working memory as shown by significant increase in the relative percentage alternations compared to untreated control MCAO rats in Y-maze. PBA also significantly decreased the transfer latency in the acquisition trial and increased in probe trial in passive avoidance task suggesting an improvement in learning and memory in MCAO rats. There was also a significant improvement in spatial learning and memory, as evidenced by the reduced escape latency in acquisition trial and the increased number of entries into the platform zone, time spent in the platform quadrant and track plot in probe trial PBA-treated MCAO rats during Morris water maze task. Conclusion: This study, thus, demonstrates the potential of PBA in ameliorating cognitive dysfunctions in focal cerebral ischemia. Since PBA is already available for the treatment of urea cycle disorders, it may also be investigated for repurposing its use in the treatment of post-stroke cognitive impairment.