Department of Senile Neurology, Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, PR China.
Eur J Pharmacol. 2010 Mar 10;629(1-3):153-8. doi: 10.1016/j.ejphar.2009.11.059. Epub 2009 Dec 21.
Insulin resistance, which may influence Alzheimer's disease, is associated with an increase in circulating advanced glycosylation end products (AGEs) and the increased expression of the receptor for AGEs (RAGE). Inhibition of AGE/RAGE system has been shown to attenuate neuronal damage. Specific ligands for peroxisome proliferator-activated receptor gamma (PPARgamma), which have proven effective in the animal models of Alzheimer's disease and other neuroinflammatory diseases, have been shown to decrease RAGE expression. Here we investigated the effect of PPARgamma agonist, pioglitazone, on cognition function and AGE/RAGE system in a rodent model of insulin resistance, the fructose-drinking rats. Six-week-old male Wistar rats were fed a standard commercial diet and water without (control) or with 10% fructose for 16weeks. The animals were randomly divided into 4 groups (n=10): non-treated and water-drinking rats (control group); pioglitazone-treated and water-drinking (control treatment group); non-treated and fructose-drinking rats (fructose group) and pioglitazone-treated and fructose-drinking rats (fructose treatment group). Pioglitazone was given at the dose of 10mg/kgd by gavage for the last 12weeks of the 16-week period. The results showed that pioglitazone treatment reduced the escape latency in Morris water maze test, decreased AGE/RAGE expression in the cerebral cortex of fructose-drinking rats. Furthermore, we found that the expression of p47phox component of NAPDH oxidase, phosphorylated nuclear factor NF-kappaB p65, tumor necrosis factor alpha and interleukin-1 beta was significantly increased in the cerebral cortex of fructose-drinking rats (P<0.001). These effects were reversed by pioglitazone treatment (P<0.01 or 0.001). Taken together, these findings suggest that the activation of AGEs-RAGE system contribute to the brain damage of insulin resistance. Pioglitazone administration can improve cognition function probably related to its effect of decreasing the activation of AGEs-RAGE system, which correlates with block of NAPDH oxidase and NF-kappaB activation in this rodent model of insulin resistance.
胰岛素抵抗可能影响阿尔茨海默病，与循环中晚期糖基化终产物（AGEs）的增加和 AGEs 受体（RAGE）的表达增加有关。抑制 AGE/RAGE 系统已被证明可以减轻神经元损伤。过氧化物酶体增殖物激活受体 γ（PPARγ）的特异性配体在阿尔茨海默病和其他神经炎症性疾病的动物模型中已被证明有效，已被证明可以降低 RAGE 的表达。在这里，我们研究了 PPARγ 激动剂吡格列酮对胰岛素抵抗啮齿动物模型（果糖饮用大鼠）认知功能和 AGE/RAGE 系统的影响。6 周龄雄性 Wistar 大鼠喂食标准商业饮食和水（对照）或 10%果糖 16 周。动物随机分为 4 组（n=10）：未处理和饮水大鼠（对照组）；吡格列酮处理和饮水（对照治疗组）；未处理和果糖饮水大鼠（果糖组）和吡格列酮处理和果糖饮水大鼠（果糖治疗组）。吡格列酮在 16 周的最后 12 周内通过灌胃给予 10mg/kgd。结果表明，吡格列酮治疗可降低 Morris 水迷宫试验中的逃逸潜伏期，降低果糖饮用大鼠大脑皮质中的 AGE/RAGE 表达。此外，我们发现果糖饮用大鼠大脑皮质中 NADPH 氧化酶的 p47phox 组成部分、磷酸化核因子 NF-κB p65、肿瘤坏死因子-α和白细胞介素-1β的表达显着增加（P<0.001）。吡格列酮治疗可逆转这些作用（P<0.01 或 0.001）。综上所述，这些发现表明 AGEs-RAGE 系统的激活导致胰岛素抵抗的脑损伤。吡格列酮给药可以改善认知功能，可能与其降低 AGEs-RAGE 系统激活的作用有关，这与该胰岛素抵抗啮齿动物模型中 NADPH 氧化酶和 NF-κB 激活的阻断有关。
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