PPAR? Agonist Pioglitazone Reverses Memory Impairment and Biochemical Changes in a Mouse Model of Type 2 Diabetes Mellitus

Aims: Pioglitazone, known as a peroxisome proliferator-activated receptor ? (PPAR?) agonist, is used to treat type 2 diabetes mellitus (T2DM). T2DM has been associated with reduced performance on numerous domains of cognitive function. Here, we investigated the effects of pioglitazone on memory impairment in a mouse model with defects in insulin sensitivity and secretion, namely high-fat diet (HFD) streptozotocin (STZ)-induced diabetic mice. Methods: ICR mice were fed with HFD for 4 weeks and then injected with a single low dose of STZ followed by continued HFD feeding for an additional 4 weeks. Pioglitazone (18 mg/kg, 9 mg/kg body weight) was orally administered for 6 weeks once daily. Y-maze test and Morris water maze test (MWM) were employed for testing learning and memory. Serum glucose, serum insulin, serum triglyceride, brain beta-amyloid peptide (A beta), brain beta-site amyloid precursor protein cleaving enzyme (BACE1), brain nuclear factor ?B (NF-?B), and brain receptor for advanced glycation end products (RAGE) were also tested. Results: The STZ/HFD diabetic mice, characterized by hyperglycemia, hyperlipemia and hypoinsulinemia, performed poorly on Y-maze and MWM hence reflecting impairment of learning and memory behavior with increases of A beta 40/A beta 42, BACE1, NF-?B, and RAGE in brain. Treatment of PPAR? agonist, pioglitazone (18 or 9 mg/kg body weight), significantly reversed diabetes-induced impairment of learning and memory behavior, which is involved in decreases of A beta 40/A beta 42 via inhibition of NF-?B, BACE1 and RAGE in brain as well as attenuation of hyperglycemia, hyperlipemia, and hypoinsulinemia. Conclusions: It is concluded that PPAR? agonist pioglitazone may be considered as potential pharmacological agents for the management of cognitive dysfunction in T2DM.