Histone Deacetylase Inhibitor MS-275 Alleviates Postoperative Cognitive Dysfunction in Rats by Inhibiting Hippocampal Neuroinflammation

Abstract

Neuroinflammation in the hippocampus plays essential roles in postoperative cognitive dysfunction (POCD). Histone deacetylases (HDACs) have recently been identified as key regulators of neuroinflammation. MS-275, an inhibitor of HDAC, has been reported to have neuroprotective effects. Therefore, the present study aimed to test the hypothesis that pretreatment with MS-275 prevents POCD by inhibiting neuroinflammation in rats. In this study, anesthesia/surgery impaired cognition, demonstrated by an increase escape latency and reduction in the number of platform crossings in Morris water maze (MWM) trials, through activating microglia neuroinflammation and decreasing PSD-95 expression. However, pretreatment with MS-275 attenuated postoperative cognitive impairment severity. Furthermore, pretreatment with MS-275 decreased activated microglia levels and increased PSD95 protein expression in the hippocampus. Pretreatment with MS-275 reduced NF-κB-p65 protein expression and nuclear accumulation as well as the neuroinflammatory response (production of proinflammatory cytokines including TNF-α and IL-1β) in the hippocampus. Additionally, MS-275 reduced HDAC2 expression and HDAC activity in the hippocampus, which were enhanced in vehicle-treated rats. These results suggest that MS-275 alleviates postoperative cognitive dysfunction by reducing neuroinflammation in the hippocampus of rats via HDAC inhibition.