ABSTRACT
Objective:To evaluate the role of hippocampal REV-ERBα in postoperative cognitive dysfunction in rats.Methods:Thirty-two SPF healthy male Sprague-Dawley rats, aged 12-14 weeks, weighing 360-380 g, were divided into 4 groups ( n=8 each) using a random number table method: control group (group C), surgery group (group S), surgery + dimethyl sulfoxide (DMSO) group (group SD), and surgery + SR9009 group (group SS). Exploratory laparotomy was performed under sevoflurane anesthesia in S, SD and SS groups.Normal saline containing 0.1% DMSO was injected into hippocampal CA1 area at 1 h before laparotomy, with 2 μl on each side in group SD, and REV-ERBα agonist SR9009 (in normal saline containing 0.1% DMSO) was injected into hippocampal CA1 area at 1 h before laparotomy, with 2 μl on each side in group S+ SR9009.Morris water maze test was performed at 1 and 3 days after operation.Rats were sacrificed at 1 h after the end of Morris water maze test on day 3 after surgery, and the hippocampal tissues were obtained for determination of the expression of REV-ERBα, Brain and Muscle ARNT-Like 1 (BMAL1) protein, synaptophysin (SYN), postsynaptic density (PSD)-95 protein and N-methyl-D-aspartate receptor 2B subunit (GRIN2B) (by Western blot) and microscopic examination of the morphology of hippocampal neurons and Nissl bodies (by Nissl staining), and the viable neurons were counted. Results:Compared with group C, the percentage of time of staying at the target quadrant was significantly decreased, and the number of crossing platform was reduced on days 1 and 3 after exploratory laparotomy, the expression of REV-ERBα, BMAL1, PSD95, SYN and GRIN2B was down-regulated, and the number of viable neurons was decreased in group S and group SD ( P<0.05). Compared with group S and group SD, the percentage of time of staying at the target quadrant and the number of crossing platform were significantly increased on days 1 and 3 after exploratory laparotomy, the expression of REV-ERBα and PSD95 was up-regulated, the number of viable neurons was increased ( P<0.05), and no significant change was found in the expression of BMAL1, SYN and GRIN2B in group SS ( P>0.05). There was no significant difference in the indexes mentioned above between group S and group SD ( P>0.05). Conclusions:Activation of REV-ERBα can improve postoperative cognitive dysfunction, and the mechanism may be related to up-regulation of PSD95 expression in hippocampus and reduction of neuronal damage in rats.
ABSTRACT
Objective:To evaluate the role of hippocampal histone deacetylases (HDACs) in perioperative neurocognitive disorders (PND) and the relationship with postsynaptic dense protein 95 (PSD95) in rats.Methods:Sixty clean-grade healthy male Sprague-Dawley rats, aged 10-14 weeks, weighing 250-280 g, were divided into 3 groups ( n=20 each) using a random number table method: control group (group C), surgery group (group S) and HDAC inhibitor MS-275 group (group MS-275). Exploratory laparotomy was performed under 3% sevoflurane anesthesia in group S. MS-275 10 mg/kg was intraperitoneally injected at 0.5 h before exploratory laparotomy in group MS-275.Morris water maze tests were performed on 1 day before surgery and 1, 3 and 7 days after surgery.Ten rats were sacrificed on 1 day after surgery, and hippocampal tissues were obtained for determination of the expression of HDAC1-3 and PSD95 protein and mRNA by Western blot and real-time polymerase chain reaction, respectively.The density of hippocampal neurons was determined by the Nissl staining. Results:Compared with group C, the postoperative escape latency was significantly prolonged, the number of crossing the original platform was decreased, the density of hippocampal neurons was decreased, the expression of HDAC2 protein and mRNA was up-regulated, and the expression of PSD95 protein and mRNA was down-regulated in group S ( P<0.05 or 0.01). Compared with group S, the postoperative escape latency was significantly shortened, the number of crossing the original platform was increased, the density of hippocampal neurons was increased, the expression of HDAC2 protein and mRNA was down-regulated, and the expression of PSD95 protein and mRNA was up-regulated in group MS-275 ( P<0.05 or 0.01). There was no significant difference in the expression of HDAC1 and HDAC3 protein and mRNA among the three groups ( P>0.05). Conclusion:HDAC2 is involved in the pathophysiological mechanism of PND by down-regulating the expression of PSD95 in rats.