吡格列酮降低海马区raf-1激酶抑制蛋白改善2型糖尿病大鼠学习记忆

目的：了解过氧化物酶体增殖物激活受体1（PPARy／）激活剂一盐酸吡格列酮对2型糖尿病模型大鼠空间记忆能力的影响，并对其可能作用的MAPK信号转导途径中raf-1激酶抑制性蛋白（RKIP）进行分析。方法：选取12周龄雄性sD大鼠26只随机分为3组（每组12只），分为对照组（Con）、2型糖尿病组（DM）、2型糖尿病＋盐酸吡格列酮组（DP）。DM组给予高脂饮食。自喂养高脂饮食20周后，通过高胰岛素正葡萄钳夹实验等证实DM组产生胰岛素抵抗；1周后，腹腔注射链脲佐菌素（STZ）27m/kg；72h后．检测空腹血糖，大于7．0mmol／L的大鼠确定为2型糖尿病大鼠。DP组大鼠给予盐酸吡格列酮10m/（kg·d），每日1次灌胃给药，Con组和DM组给予生理盐水每日一次灌胃；所有实验动物在继续喂养8周后行水迷宫实验后处死，应用蛋白印迹及逆转录PCR方法检测海马组织中RKIP蛋白、基因水平相对含量变化。结果：Con组和DP组大鼠海马背侧RKIP蛋白含量及mRNA含量均较DM组水平下降，差异具有统计学意义（P〈0．05）。结论：通过降低RKIP含量，进一步导致海马MAPK通路活化，可能是吡咯列酮改善2型糖尿病模型老年大鼠空间记忆能力的机制之一。

Pioglitazone (PGZ) improves learning and memory ability in DM rats by down-regulating RKIP in hippocampus

Objective： To study the effects of pioglitazone （PGZ）, a peroxisome proliferator-activated receptor ~ （PPAR~/） agonist, on the spatial memory of type 2 diabetes rats and to determine the expression of Raf kinase inhibitor protein （RKIP） in MAPK signaling pathway which PGZ probably acts on. Methods：12-week old male SD rats were randomized into three groups （n = 12 each） ： the control group （group Con）, DM group and DM plus Pioglitazone group （group DP）. The rats in DM or DP group were fed with high-fat diet, and were confirmed to have insulin resistance by hyperglycaemic glucose clamp experiments at week 20 weeks of high-fat feeding. One week later, the rats on high-fat diet received intraperitoneal injection of 27 mg/kg streptozocin （STZ）. After 72h, rats with fasting blood glucose （FBG） 〉 7.0 mmol/L were considered to have type 2 diabetes mellitus. The DP group received once-daily gavage of mg/（ kg ~ d）pioglitazone hydrochloride, while rats in Con and DM groups were given once-daily garage ~f normal saline. All the rats were fed for 8 more weeks and then sacrificed after water maze experiment. Western blotting and RT-PCR were used to detect the change in expression of RKIP mRNA and proteins in hippocampus. Results：The groups Con and DP showed significantly lowered expression levels of RKIP mRNA and protein in dorsal hippocampus as compared with DM group （ P 〈 0. 05 ）. Conclusion： Pioglitazone （PGZ） may improve the spatial memory in rats with type 2 diabetes mellitus, partly through down-regulation of RKIP and hence activation of MAPK signaling pathway in hippocampus.