Pioglitazone ameliorates memory deficits in streptozotocin-induced diabetic mice by reducing brain beta-amyloid through PPAR gamma activation

作者：Liu, Li-ping; Yan, Tian-hua; Jiang, Li-ying; Hu, Wei; Hu, Meng; Wang, Chao; Zhang, Qian; Long, Yan; Wang, Jiang-qing; Li, Yong-qi; Hu, Mei; Hong, Hao^*

来源：Acta Pharmacologica Sinica, 2013, 34(4): 455-463.

DOI：10.1038/aps.2013.11

• diabetes mellitus
• pioglitazone
• learning memory
• hippocampus
• cortex
• PPAR gamma
• beta-amyloid
• BACE1
• NF-kappa B
• receptor for advanced glycation end products
• APP

Aim: To examine the effects of pioglitazone, a PPAR gamma agonist, on memory performance and brain amyloidogenesis in streptozotocin (STZ)-induced diabetic mice.
Methods: ICR male mice were injected with STZ (150 mg/kg, iv) to induce experimental diabetes. Pioglitazone (9 and 18 mg.kg(-1).d(-1), po) was administered for 6 weeks. Passive avoidance and Morris water maze (MWM) tests were used to evaluate cognitive function. The blood glucose and serum insulin levels were detected using the glucose oxidase method and an ELISA assay, respectively. beta-amyloid (A beta), beta-amyloid precursor protein (APP), beta-amyloid precursor protein cleaving enzyme 1 (BACE1), NF-kappa B p65, the receptor for advanced glycation end products (RAGE) and PPAR gamma in the brains were analyzed using Western blotting assays.
Results: The STZ-induced diabetic mice characterized by hyperglycemia and hypoinsulinemia performed poorly in both the passive avoidance and MWM tests, accompanied by increased A beta(1-40)/A beta(1-42), APP, BACE1, NF-kappa B p65 and RAGE levels and decreased PPAR. level in the hippocampus and cortex. Chronic pioglitazone treatment significantly ameliorated the memory deficits and amyloidogenesis of STZ-induced diabetic mice, and suppressed expression of APP, BACE1, RAGE and NF-kappa B p65, and activated PPAR gamma in the hippocampus and cortex. However, pioglitazone did not significantly affect blood glucose and insulin levels.
Conclusion: Pioglitazone ameliorates memory deficits in STZ-induced diabetic mice by reducing brain A beta level via activation of PPAR gamma, which is independent of its effects on blood glucose and insulin levels. The results suggest that pioglitazone may be used for treating the cognitive dysfunction in type 1 diabetes mellitus.

• 出版日期2013-4
• 单位安徽医科大学; 中国药科大学