Repositioning Gliptins for Parkinson's Disease Treatment

 描述（由申请人提供）：二肽基蛋白酶-4（DPP-4）抑制剂-也称为格列汀-广泛用于有效治疗2型糖尿病，以安全调节血糖水平。DPP-4是负责内源性肠促胰岛素、胰高血糖素样肽样肽-1（GLP-1）和葡萄糖依赖性促胰岛素多肽（GIP）代谢的关键酶，我们假设其在脑中的水平升高将在帕金森病（PD）的细胞和体内啮齿动物模型中提供神经营养/神经保护作用。在评价几种DPP-4抑制剂时，啮齿类动物的脑和血浆肠促胰岛素水平确实显著升高，这导致在充分表征的急性啮齿类动物PD模型中帕金森综合征改善和脑多巴胺水平升高，并降低体外细胞模型中的毒性。我们拟定的研究将通过在慢性毒素和遗传学啮齿动物PD模型中评估DPP-4抑制剂西格列汀，扩展我们对二肽基蛋白酶-4（DPP-4）抑制剂作为帕金森病新治疗策略的评价。在这些慢性啮齿动物PD模型中，我们将通过测量行为、生化和免疫细胞化学参数来评价西格列汀的神经恢复活性。此外，将进行机制研究，以将西格列汀疗效与ER应激/未折叠蛋白反应、线粒体功能和神经炎症分析相关联。

 DESCRIPTION (provided by applicant): Dipeptidyl protease-4 (DPP-4) inhibitors - also known as gliptins - are widely used in the effective treatment of type 2 diabetes to safely regulate bloo glucose levels. DPP-4 is the key enzyme responsible for the metabolism of the endogenous incretins, glucagon-like peptide-like-peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) whose elevated levels in brain, we hypothesized, would provide neurotrophic/neuroprotective actions in cellular and in vivo rodent models of Parkinson's disease (PD). On evaluating several DPP-4 inhibitors, brain and plasma incretin levels were, indeed, substantially elevated in rodents, and this resulted in amelioration of Parkinsonism and elevations in brain dopamine levels in a well- characterized acute rodent PD model as well as reducing toxicity in vitro cellular model. Our proposed studies will extend our evaluation of dipeptidyl protease-4 (DPP-4) inhibitors as a new treatment strategy for Parkinson's disease by assessing the DPP-4 inhibitor sitagliptin in chronic toxin and genetics rodent PD models. In these chronic rodent PD models, we will evaluate neurorestorative activity of sitagliptin by measuring behavioral, biochemical, and immunocytochemical parameters. In addition, mechanistic studies will be carried out to correlate sitagliptin efficacy with analysis of ER stress/unfolded protein responses, mitochondrial function and neuroinflammation.