Effect of pioglitazone on insulin resistance in fructose-drinking rats correlates with AGEs/RAGE inhibition and block of NAPDH oxidase and NF kappa B activation

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 γ (PPARγ), 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 PPARγ 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 16 weeks. 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 10 mg/kg d by gavage for the last 12 weeks 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-κB 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-κB activation in this rodent model of insulin resistance.