Effects Of Histone Deacetylase On Cognitive Deficits In A Mouse Model Of Sepsis-associated Encephalopathy

Purpose:To investigate whether histone deacetylase (HDAC) inhibitor valproic acid (VPA) can reverse cognitive deficits and determine the beneficial effects of VPA involved in brain-derived neurotrophic factor (BDNF)-TrkB signaling pathway in a mouse model of septic encephalopathy.Method:Mouse model of septic encephalopathy was induced in adult male mice by cecal ligation and puncture (CLP). Animals were randomly assigned to Sham+Saline, Sham+VPA, CLP+Saline, CLP+VPA, and CLP+VPA+K252a group. Behavioral tests were performed 14 or 28 d after operation. The expression of IL-1β, Activated caspase-3, HDAC2, acetyl-H3K9, acetyl-H4K12, BDNF, pTrkB, and PSD95 were evaluated after Morris water maze. Effects of TrkB antagonist K252a on the beneficial effects of class 1 HDAC inhibitor VPA were also evaluated.Results:Chronic VPA treatment significantly improves learning and memory in sepsis mice, which was associated with reduced hippocampal HDAC2, IL-1β and Activated caspase-3 expression and increased acetyl-H3K9, acetyl-H4K12, BDNF, pTrkB, PSD95, and synapses. However, the beneficial effects of VPA were abolished by TrkB antagonist K252a.Conclusion:HDAC is involved in the pathogenesis of SAE. Chronic treatment of class I HDAC inhibitor VPA reverses cognitive deficits probably via activating BDNF-TrkB signaling pathway in a mouse model of septic encephalopathy.