Role of Ca 2+-CaMKⅡ-CREB signaling pathway in U50488H-induced reduction of CPB-caused perioperative neurocognitive disorders in rats / 中华麻醉学杂志

ABSTRACT

Objective:To evaluate the role of calcium-calmodulin-dependent protein kinase Ⅱ-cyclic adenylate response element binding protein (Ca 2 + -CaMK Ⅱ-CREB) signaling pathway in U50488H-induced reduction of cardiopulmonary bypass (CPB)-caused perioperative neurocognitive disorders in rats. Methods:Forty clean-grade male adult Sprague-Dawley rats, weighing 350-400 g, were divided into 4 groups ( n=10 each) using a random number table method: control group (S group), CPB group (C group), CPB plus by κ-opioid receptor agonist U50488H group (U group), and CPB plus specific CaMKⅡ antagonist KN93 plus U50488H group (K group). Only the arteriovenous catheter was placed in S group, and the blood-free pre-filled cardiac CPB model was established in the other groups.U50488H 1.5 mg/kg was intravenously injected at 30 min before CPB in group U. In group K, 10 μmol/L KN93 5 μl was injected into left lateral cerebral ventricle at 60 min before CPB, and U50488H 1.5 mg/kg was intravenously injected at 30 min before CPB.Morris water maze test was used to assess cognitive function on 3rd day after operation.The rats were then sacrificed, and hippocampal tissues were obtained for determination of the expression of phosphorylated CaMKⅡ (p-CaMKⅡ), phosphorylated CREB (p-CREB) and brain-derived neurotrophic factor (BDNF) (by Western blot) and expression of CaMKⅡ, CREB and BDNF mRNA (by real-time polymerase chain reaction). Results:Compared with S group, the escape latency was significantly prolonged, the number of crossing original platforms was decreased, and the expression of p-CaMKⅡ, p-CREB, CaMKⅡmRNA, CREB mRNA and BDNF protein and mRNA was down-regulated in C, U group and K groups ( P<0.05). Compared with group C, the escape latency was significantly shortened, the number of crossing original platforms was increased, and the expression of p-CaMKⅡ, p-CREB, CaMKⅡmRNA, CREB mRNA and BDNF protein and mRNA was up-regulated in group U ( P<0.05), and no significant change was found in the parameters mentioned above in group K ( P>0.05). Compared with group U, the escape latency was significantly prolonged, the number of crossing original platforms was decreased, and the expression of p-CaMKⅡ, p-CREB, CaMKⅡmRNA, CREB mRNA and BDNF protein and mRNA was down-regulated in group K ( P<0.05). Conclusion:The mechanism by which U50488H reduces CPB-caused perioperative neurocognitive disorders is related to activating the Ca 2 + -CaMK II-CREB signaling pathway in rats.