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

SUMMARY  Aims: Pioglitazone, known as a peroxisome proliferator‐activated receptor γ (PPARγ) 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 β‐amyloid peptide (Aβ), brain β‐site amyloid precursor protein cleaving enzyme (BACE1), brain nuclear factor κB (NF‐κB), 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 Aβ40/Aβ42, BACE1, NF‐κB, and RAGE in brain. Treatment of PPARγ 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 Aβ40/Aβ42 via inhibition of NF‐κB, BACE1 and RAGE in brain as well as attenuation of hyperglycemia, hyperlipemia, and hypoinsulinemia. Conclusions: It is concluded that PPARγ agonist pioglitazone may be considered as potential pharmacological agents for the management of cognitive dysfunction in T2DM.