Role of hippocampal PKMζ/KCC2 pathway in propofol postconditioning-induced long-term cerebral protection following cerebral ischemia-reperfusion in rats / 中华麻醉学杂志

ABSTRACT

Objective To investigate the role of hippocampal protein kinase Mζ (PKMζ)/potassium-chloride cotransporter-2 (KCC2) pathway in propofol postconditioning-induced long-term cerebral protection following cerebral ischemia-reperfusion (I/R) in rats.Methods Sixty adult male Sprague-Dawley rats, weighing 250-280 g, were randomly divided into 5 groups (n =12 each) sham operation group (group S), cerebral I/R group (group I/R), propofol post-conditioning group (group P) , PKMζ inhibitor ZIP+cerebral I/R group (group Z+I/R) , and ZIP + propofol postconditioning group (group Z + P).Cerebral ischemia was induced by 1 h middle cerebral artery occlusion, followed by reperfusion in anesthetized rats.Propofol 20 mg · kg-1 · h-1was intravenously infused for 2 h in P and Z+P groups, and the equal volume of normal saline was given for 2 h in I/R and Z+I/R groups.In Z+P and Z+ I/R groups, ZIP 0.5 μmol/L was injected intravenously at 15 min before reperfusion.Modified Neurological Severity Score (mNSS) was assessed at 28 days of reperfusion.After the end of behavioral tests, the hippocampi were removed for determination of GABAergic interneurons GAD67/KCC2 positive neuron count in the hippocampal CA1 region (by using immunofluorescent staining), and PKMζ and phosphorylated KCC2 (p-KCC2) expression (by Western blot).Results Compared with group S, mNSS was significantly increased, GAD67/KCC2 positive neuron count was decreased, and the expression of PKMζ and p-KCC2 was down-regulated in I/R, P and Z+P groups (P＜0.05).Compared with group I/R, mNSS was significantly decreased, GAD67/KCC2 positive neuron count was increased, and the expression of PKMζ and p-KCC2 was up-regulated in group P, and mNSS was significantly increased, GAD67/KCC2 positive neuron count was decreased, and the expression of PKMζ and p-KCC2 was down-regulated in group Z+I/R (P＜0.05).Compared with group P, mNSS was significantly increased, GAD67/KCC2 positive neuron count was decreased, and the expression of PKMζ and p-KCC2 was down-regulated in group Z+P (P＜0.05).Conclusion The mechanism underlying propofol postconditioning-induced long-term cerebral protection following cerebral I/R may be related to activation of hippocampal PKMζ/KCC2 pathway in rats.