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Abstract The aim of the present study was to investigate, the possible protective and enhancing effect of exenatide and pioglitazone alone and in combinations on cognitive decline through observing their effect on learning ability using the water maze and radial maze tasks and evaluating the microglia cell expression and oligomer over production in insulin resistant rats’brain. Insulin resistance was induced by giving 60% fructose syrup for 12 weeks to male wistar rats. At the 5th week, rats received two exenatide doses (10 or 20 μg/kg) alone and in combination with pioglitazone (10 mg/kg). The current study showed that both single and combination treatment enhancing learning and behavior abilities in rats through significant reduction in the beta amyloid oligomer level and down regulation of the microglia cell expression and dedicated that the single treatment for both exenatide and pioglitazone was sufficient to enhance memory dysfunction in insulin resistant rats. Though these two medications may be considered promising agents in retarding early symptoms of memory dysfunction in patients with insulin resistance. |