Class Ⅱb Histone Deacetylase Participates in Postoperative Cognitive Dysfunction in Elderly Mice via HSP90/GR Signaling Pathway

Objective: Multiple factors contribute to the development of perioperative neurocognitive disorders (PND). This study was designed to investigate whether group class Ⅱb histone deacetylases were involved in the formation of postoperative cognitive dysfunction in elderly mice by regulating the degree of acetylation of HSP90 and related protein functions and quantities. Methods: C57BL/6J male mice were randomly divided into five groups: control naive (group Control), anesthesia (group Anesthesia, referred to as anesthesia group), anesthesia plus splenectomy surgery (group Surgery), anesthesia plus splenectomy surgery plus the inhibitor ACY-1215 (group Ricolinostat), and anesthesia plus splenectomy surgery plus dissolvent (group Vehicles). After the mice were trained for Morris Water Maze (MWM) test for five days, anesthesia and operational surgery were carried out on the following day. Cognitive function was assessed on 1st and 3rd days post-surgery. The hippocampi were harvested on days 1, 3, and 7 post-surgeries for quantitative RT-PCR, Western blots, and ELISA assays. Results: The mice with the splenectomy surgery displayed impaired spatial learning and memory in the MWM test, which marked the increase of the HDAC6 and deacetylated its downstream protein HSP90 at the molecular level. The hippocampus of surgical groups showed a decrease in acetylated HSP90, a rise in GR-HSP90 association, and an increase in GR translocation. The HDAC6 inhibitor can partly reverse the effect of the operation. Conclusions: Abdominal surgery may impair hippocampal spatial memory, possibly through the increased HDAC6- triggered increase in the function of HSP90 and consequent strengthen in the negative role of steroids in cognitive function. Targeting HDAC6 may provide a potential avenue in the treatment of the impairment of cognitive function after surgery.