吡格列酮对胰岛素抵抗大鼠认知功能及脑组织AGE-RAGE损伤途径的影响

目的探讨吡格列酮（PIO）对高果糖诱发的胰岛素抵抗（IR）大鼠认知功能及脑组织糖基化终末产物（AGEs）-AGEs受体（RAGE）损伤途径的影响。方法45只6～8周龄Wistar大鼠分为正常对照组（NC组）、胰岛素抵抗组（IR组）、吡格列酮组（PIO组），后两组给予饮用10%的果糖水建立胰岛素抵抗模型，模型成功的PIO组给予吡格列酮干预12周后，采用Morris水迷宫试验检测逃避潜伏期；免疫荧光技术检测脑组织AGEs表达；Western blotting检测脑组织过氧化物酶体增殖物激活受体γ（PPARγ）、RAGE、磷酸化核转录因子-κB(Phospho NF κB)的蛋白表达。结果① IR组与PIO组逃避潜伏期较NC组明显延长，差异有统计学意义(P＜0.01或P＜0.05)；PIO组逃避潜伏期较IR组明显缩短，差异有统计学意义(P＜0.01)。②　免疫荧光检测结果显示，PIO组、IR组AGEs表达较NC组明显增强；与IR组相比，PIO组AGEs的表达较弱。③ 与NC组相比，IR组和PIO组磷酸化NF κB、RAGE的蛋白表达升高(P＜0.01)，PPARγ表达降低（P＜0.05）；与IR组相比，PIO组磷酸化NF κB、RAGE的蛋白表达明显下降(P＜0.01)；PPARγ表达增加（P＜0.05）。结论胰岛素抵抗大鼠脑组织AGEs RAGE系统活性增强可能是脑损害机制之一，吡格列酮能改善胰岛素抵抗大鼠的认知功能，抑制AGEs RAGE通路活性，发挥脑保护作用。

Effects of Pioglitazone on cognition function and AGEs-RAGE system in insulin resistance in rats

To explore the effects of Pioglitazone on cognition function and AGEs-RAGE system in insulin resistant rats. Methods 6-8 week Wistar rats were fed with fructose to develop insulin resistant(IR) models for 4 weeks, then IR rat models were randomly divided into the IR group (n=13) and the Pioglitazone (PIO) group (n=13). Rats in the PIO group were given Pioglitazone 10?mg/(kg·d) by gavage for 12 weeks. The cognition ability of rats was assayed with the Morris water maze test. The expressions of advanced glycation end products were determined by immunofluorescence. Western blotting was used to detect the expression of PPARγ, Phospho -NF-κB and RAGE protein. Results① The Morris water maze test showed that escape latency was longer in the IR group and the PIO group than that in the normal control (NC) group (P＜0.01, P＜0.05), and it was shorter in the PIO group compared with the IR group(P＜0.01). ②　The expression of AGEs protein in the IR group and the PIO group was higher than that in the NC group, also it was significantly decreased in the PIO group compared with the IR group. ③　The expressions of RAGE and Phospho-NF-κB protein in the IR and PIO groups were higher than those in the NC group .Compared with the IR group, the expressions of RAGE and Phospho-NF-κB in the PIO group were significantly decreased. The expression of PPARγ protein in the IR and PIO groups was lower than in the NC group（P＜0.05）, however compared with the IR group, the expression of PPARγ in the PIO group was significantly increased（P＜0.05）. ConclusionThe strengthening of the AGEs RAGE system activation is a possible mechanism of brain damage. Pioglitazone therapy can ameliorate cognition function of IR rats which is probably related to its effect on decreasing the AGEs -RAGE system activation.