Repositioning Gliptins for Parkinson's Disease Treatment

重新定位格列汀治疗帕金森病

• 批准号: 9276809
• 负责人: Barry J Hoffer
• 金额: $ 34.28万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-30 至 2020-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9276809
• 关键词: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Acute; Adverse effects; Animal Model; Backcrossings; Behavioral; Biochemical; Brain; Breeding; Cell model; Cells; Chronic; Clinical; Clinical Trials; Clinical assessments; Complement; Corpus striatum structure; Data; Dipeptidyl Peptidases; Disease model; Distress; Dopamine; Dose; Drug usage; Dysplasia; Enzyme Inhibitor Drugs; Enzymes; Evaluation; Gastric Inhibitory Polypeptide; Gene Targeting; Genetic; Glucose; Heat shock proteins; Histologic; Human; Hydroxydopamines; Hypoglycemia; Impairment; In Vitro; Investigation; Kidney; Lesion; Measures; Metabolism; Methods; Mitochondria; Modeling; Mus; Nerve Degeneration; Nerve Regeneration; Neuroimmune; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Oral; Pancreatitis; Parkinson Disease; Parkinsonian Disorders; Pathway interactions; Peptide Hydrolases; Peptides; Pharmaceutical Preparations; Physiological; Plasma; Property; Proteins; Rattus; Reporting; Rodent; Rodent Model; Role; SERPINA4 gene; Stress; Substantia nigra structure; Therapeutic; Time; Tissues; Toxic effect; Toxin; Transgenic Organisms; Translating; Up-Regulation; acute pancreatitis; alpha synuclein; behavior measurement; clinical risk; clinical translation; clinically relevant; effective therapy; exenatide; gastric inhibitory polypeptide receptor; glucagon like peptide; glucagon-like peptide; glucagon-like peptide 1; in vivo; inhibitor/antagonist; insulin secretion; median forebrain bundle; men' s group; mimetics; mouse synuclein alpha; nerve injury; neurochemistry; neuroinflammation; neuroprotection; neurorestoration; pre-clinical; preclinical study; public health relevance; receptor; response; stress protein; treatment strategy

 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.

 描述(申请人提供)：二肽基蛋白酶-4(DPP-4)抑制剂-也称为格列普汀-被广泛用于安全地调节血糖水平的2型糖尿病的有效治疗中。DPP-4是负责内源性胰岛素代谢的关键酶，即胰升糖素样肽-1(GLP-1)和葡萄糖依赖的促胰岛素多肽(GIP)，我们推测，它们在脑内的水平升高将在细胞和体内帕金森病(PD)啮齿动物模型中提供神经营养/神经保护作用。在评估几种DPP-4抑制剂时，啮齿动物的大脑和血浆中的胰岛素水平确实大幅上升，这导致了帕金森病的改善和脑内多巴胺水平的升高，并降低了体外细胞模型的毒性。我们建议的研究将通过在慢性毒素和遗传学的啮齿动物PD模型中评估DPP-4抑制剂Sitagliptin来扩展我们对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帕金森病模型中，我们将通过测量行为、生化和免疫细胞化学参数来评估西格列汀的神经恢复活性。此外，还将进行机制研究，以将西格列汀的疗效与内质网应激/未折叠蛋白反应、线粒体功能和神经炎症的分析联系起来。