氯氨酮减轻高血糖大鼠脑缺血所致的神经元凋亡

Role of ketamine in decreasing neuronal apoptosis caused by brain ischemia in rats with hyperglycemia

目的:探讨氯氨酮减轻高血糖加重脑缺血损伤的机制.方法:在正常血糖、高血糖以及氯氨酮干预条件下,制作大鼠全脑缺血15 m in,再灌注0.5,1和3 h模型.通过免疫组化和免疫印迹技术对比研究细胞外信号调节激酶1/2(ERK1/2)的磷酸化,同时采用末端脱氧核苷酸转移酶介导的dUTP原位切口末端标记方法观察神经细胞凋亡.结果:正常血糖组大鼠全脑再灌注0.5 h扣带皮质和海马CA1及CA3区的ERK1/2磷酸化明显增加;在高血糖组缺血再灌注后0.5 h,扣带皮质和海马CA3区的ERK1/2磷酸化明显高于正常血糖组,持续到再灌注后的3 h;氯氨酮组可见由高血糖诱导的ERK1/2磷酸化被抑制.同时,磷酸化ERK1/2的程度与脑组织损伤结果一致.结论:高血糖可通过ERK1/2信号转导通路加重缺血性脑损伤,氯氨酮通过阻断NMDA受体,改善钙离子异常而抑制高血糖介导的ERK1/2磷酸化,从而减轻高血糖加重缺血性脑损伤.

AIM： To investigate the mechanism by which ketamine reduces the aggravation of hyperglycemia-induced cerebral ischemic lesion. METHODS ： Rats with normoglycemia, hyperglycemia, or hyperglycemia pretreated with ketamine injection were subjected to 15 min of global brain ischemia, and then reperfused for 0.5, 1, and 3 h, respectively. Phosphorylation of extracellular signal-regulated kinase （ERK） 1/2 was assessed by immunohistochemistry and Western blot analysis. Meanwhile, the neuronal apoptosis was observed by TdT-mediated dUTP nick-end labeling （TUNEL）. RESULTS： The phosphorylation of ERK1/2 in the regions of cingulum cortex, hippocampus CA1 and CA3, were significantly increased in ischemic rats with normoglycemia reperfused for 0.5 h. Compared to the normoglycemic group, the phosphorylation of ERK1/2 in the regions of cingulum cortex and hippocampus CA3 were also significantly increased in hyperglycemic group reperfused for 0.5 h, which lasted to 3 h of reperfusion. However, this augmentation of phosphorylation was depressed by ketamine administration in hyperglycemic rats. The extent of ERK1/2 phosphorylation was consistent with the ischemic brain lesions, observed by histology as neuronal apoptosis. CONCLUSION： Hyperglycemia may increase the ischemic insult via the modulation of ERK1/2 signal transduction pathways. Ketamine improves the aggravation of hyperglycemia-induced cerebral ischemic lesion. This is probably mediated by inhibition of NMDA-mediated calcium influx, and hyperglycemia-induced phosphorylation of ERK1/2.