Repositioning Gliptins for Parkinson's Disease Treatment

重新定位格列汀治疗帕金森病

基本信息

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
项目类别：
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&apos 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

项目摘要

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（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 是负责血糖水平的关键酶。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) 的代谢，其水平升高我们进化出的大脑将在帕金森病 (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。在评估几种 DPP-4 抑制剂时，啮齿动物的大脑和血浆肠促胰素水平确实显着升高，这导致了。在充分表征的急性啮齿动物帕金森病模型中改善帕金森病和提高脑多巴胺水平以及降低体外细胞模型的毒性我们提出的研究将扩展我们对二肽基的评估。通过评估慢性毒素和遗传啮齿类帕金森病模型中的 DPP-4 抑制剂西他列汀，将蛋白酶 4 (DPP-4) 抑制剂作为帕金森病的新治疗策略。在这些慢性啮齿类帕金森病模型中，我们将通过测量来评估西格列汀的神经恢复活性。此外，还将进行机制研究，将西格列汀功效与内质网应激/未折叠蛋白反应、线粒体功能和功能的分析联系起来。神经炎症。