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.

Public Health Relevance

Our initial dipeptidyl protease-4 (DDP-4) inhibitor studies defined this drug class as beneficial in well characterized cellular and rodent acute Parkinson's disease (PD) models. Our aim is to evaluate whether the beneficial actions of clinically relevant and doses of DPP-4 inhibitors to elevate incretin GIP and GLP-1) levels will translate to chronic rodent PD models as a key step to de-risk clinical translation. If successful, our proposed studies will lay the essential groundwork for a clinical trial of the DPP-4 inhibitor sitagliptin i PD - by defining a drug dose for central incretin actions.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS094152-01
Application #
9002668
Study Section
Drug Discovery for the Nervous System Study Section (DDNS)
Program Officer
Sieber, Beth-Anne
Project Start
2015-09-30
Project End
2018-06-30
Budget Start
2015-09-30
Budget End
2016-06-30
Support Year
1
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Case Western Reserve University
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Chen, Yuan-Hao; Kuo, Tung-Tai; Kao, Jen-Hsin et al. (2018) Exercise Ameliorates Motor Deficits and Improves Dopaminergic Functions in the Rat Hemi-Parkinson's Model. Sci Rep 8:3973
Chen, Shuchun; Yu, Seong-Jin; Li, Yazhou et al. (2018) Post-treatment with PT302, a long-acting Exendin-4 sustained release formulation, reduces dopaminergic neurodegeneration in a 6-Hydroxydopamine rat model of Parkinson's disease. Sci Rep 8:10722
Yu, Yu-Wen; Hsueh, Shih-Chang; Lai, Jing-Huei et al. (2018) Glucose-Dependent Insulinotropic Polypeptide Mitigates 6-OHDA-Induced Behavioral Impairments in Parkinsonian Rats. Int J Mol Sci 19:
Lu, Tao; Kim, Paul P; Greig, Nigel H et al. (2017) Dopaminergic Neuron-Specific Deletion of p53 Gene Attenuates Methamphetamine Neurotoxicity. Neurotox Res 32:218-230
Lu, Tao; Kim, Paul; Luo, Yu (2017) Tp53 gene mediates distinct dopaminergic neuronal damage in different dopaminergic neurotoxicant models. Neural Regen Res 12:1413-1417
Kim, Dong Seok; Choi, Ho-Il; Wang, Yun et al. (2017) A New Treatment Strategy for Parkinson's Disease through the Gut-Brain Axis: The Glucagon-Like Peptide-1 Receptor Pathway. Cell Transplant 26:1560-1571
Zhou, Xiaofei; Pace, Jonathan; Filichia, Emily et al. (2016) Effect of the sonic hedgehog receptor smoothened on the survival and function of dopaminergic neurons. Exp Neurol 283:235-45
Wang, Jin-Ya; Huang, Ya-Ni; Chiu, Chong-Chi et al. (2016) Pomalidomide mitigates neuronal loss, neuroinflammation, and behavioral impairments induced by traumatic brain injury in rat. J Neuroinflammation 13:168
Qi, Xin; Davis, Brandon; Chiang, Yung-Hsiao et al. (2016) Dopaminergic neuron-specific deletion of p53 gene is neuroprotective in an experimental Parkinson's disease model. J Neurochem 138:746-57
Yang, Ling-Yu; Greig, Nigel H; Huang, Ya-Ni et al. (2016) Post-traumatic administration of the p53 inactivator pifithrin-? oxygen analogue reduces hippocampal neuronal loss and improves cognitive deficits after experimental traumatic brain injury. Neurobiol Dis 96:216-226

Showing the most recent 10 out of 11 publications