Parkinson's disease (PD) is a slow, progressive, debilitative, neurodegenerative disease, which has no cure. The current pharmacological therapies only temporarily mask symptoms, but do not protect neurons from further degeneration. Furthermore, chemotherapeutic agents often cause severe adverse effects and reduce the effectiveness of treatment. Numerous clinical reports have suggested that endurance exercise can slow down disease progression, and add years of independent and quality life to PD patients, or even improve the delivery and efficacy of L-DOPA treatment. Exercise therapy, or in conjunction with drug therapy at early onset of disease state, have been highly advocated by recent clinical trials. The potential health benefit and neurological mechanisms of action for exercise on PD rehabilitation have not been rigorously tested in the laboratory animal models. This research is designed to elucidate the impact of endurance exercise training on nigrostriatal dopamine (DA) neuron plasticity using a slow, progressive, and neurodegenerative mouse model of PD developed and characterized by our laboratory. This model is established based on a regimen of chronic 1-Methyl-4-phenyl - 1,2,3,6-tetrahydropyridine (MPTP) injections co-administered with probenecid, a drug that inhibits the peripheral and neuronal clearance of MPTP and potentiates the neurotoxicity of MPTP. In this model, we observed a marked decrease of nigrostriatal DA function within one week after treatment and remained low for 6 months. The animal also shows a gradual loss of substantia nigra (SN) neurons, decline of motor activity, and an accumulation of c-synuclein-immunoreactive inclusions in the SN. We further present in the application our preliminary findings supporting the feasibility and potential neuromodulatory role of endurance exercise on enhancing nigrostriatal DA transmission and PD rehabilitation using this model. In this research, we will test the following hypotheses centered on the endurance exercise, when administered at an early stage in the parkinsonian (PK) mice, will 1) improve their mobility and physical rehabilitation, 2) improve the efficacy of L-DOPA, 3) produce these effects by mechanistically causing an elevation of BDNF expression, an increase in the differentiation of DA progenitor cells, and an enhanced DA transmission and plasticity in the nigrostriatal neurons. Findings from this research should provide new insight into the development of alternative therapeutic approaches for enhancing the conventional pharmacological treatment and rehabilitation of PD. Potential benefits for using such a synergistic approach in managing PD would likely reduce the risk of drug toxicity and lower the cost of health care for these patients.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZHD1-DSR-A (23))
Program Officer
Chen, Daofen
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Houston
Schools of Pharmacy
United States
Zip Code
Patki, Gaurav; Lau, Yuen-Sum (2011) Impact of exercise on mitochondrial transcription factor expression and damage in the striatum of a chronic mouse model of Parkinson's disease. Neurosci Lett 505:268-72
Patki, Gaurav; Lau, Yuen-Sum (2011) Melatonin protects against neurobehavioral and mitochondrial deficits in a chronic mouse model of Parkinson's disease. Pharmacol Biochem Behav 99:704-11
Lau, Yuen-Sum; Patki, Gaurav; Das-Panja, Kaberi et al. (2011) Neuroprotective effects and mechanisms of exercise in a chronic mouse model of Parkinson's disease with moderate neurodegeneration. Eur J Neurosci 33:1264-74
Pothakos, Konstantinos; Kurz, Max J; Lau, Yuen-Sum (2009) Restorative effect of endurance exercise on behavioral deficits in the chronic mouse model of Parkinson's disease with severe neurodegeneration. BMC Neurosci 10:6
Barber-Singh, Jennifer; Seo, Byoung Boo; Nakamaru-Ogiso, Eiko et al. (2009) Neuroprotective effect of long-term NDI1 gene expression in a chronic mouse model of Parkinson disorder. Rejuvenation Res 12:259-67
Ahmad, S Omar; Park, Ji-Hyuk; Stenho-Bittel, Lisa et al. (2009) Effects of endurance exercise on ventral tegmental area neurons in the chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and probenecid-treated mice. Neurosci Lett 450:102-5
Kurz, Max J; Pothakos, Konstantinos; Jamaluddin, Sakeena et al. (2007) A chronic mouse model of Parkinson's disease has a reduced gait pattern certainty. Neurosci Lett 429:39-42
Al-Jarrah, M; Pothakos, K; Novikova, L et al. (2007) Endurance exercise promotes cardiorespiratory rehabilitation without neurorestoration in the chronic mouse model of parkinsonism with severe neurodegeneration. Neuroscience 149:28-37
Novikova, L; Garris, B L; Garris, D R et al. (2006) Early signs of neuronal apoptosis in the substantia nigra pars compacta of the progressive neurodegenerative mouse 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/probenecid model of Parkinson's disease. Neuroscience 140:67-76
Lau, Yuen-Sum; Novikova, Lesya; Roels, Christina (2005) MPTP treatment in mice does not transmit and cause Parkinsonian neurotoxicity in non-treated cagemates through close contact. Neurosci Res 52:371-8