Restorative effect of endurance exercise on behavioral deficits in the chronic mouse model of Parkinson's disease with severe neurodegeneration.
BACKGROUND
Animal models of Parkinson's disease have been widely used for investigating the mechanisms of neurodegenerative process and for discovering alternative strategies for treating the disease. Following 10 injections with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, 25 mg/kg) and probenecid (250 mg/kg) over 5 weeks in mice, we have established and characterized a chronic mouse model of Parkinson's disease (MPD), which displays severe long-term neurological and pathological defects resembling that of the human Parkinson's disease in the advanced stage. The behavioral manifestations in this chronic mouse model of Parkinson's syndrome remain uninvestigated. The health benefit of exercise in aging and in neurodegenerative disorders including the Parkinson's disease has been implicated; however, clinical and laboratory studies in this area are limited. In this research with the chronic MPD, we first conducted a series of behavioral tests and then investigated the impact of endurance exercise on the identified Parkinsonian behavioral deficits.


RESULTS
We report here that the severe chronic MPD mice showed significant deficits in their gait pattern consistency and in learning the cued version of the Morris water maze. Their performances on the challenging beam and walking grid were considerably attenuated suggesting the lack of balance and motor coordination. Furthermore, their spontaneous and amphetamine-stimulated locomotor activities in the open field were significantly suppressed. The behavioral deficits in the chronic MPD lasted for at least 8 weeks after MPTP/probenecid treatment. When the chronic MPD mice were exercise-trained on a motorized treadmill 1 week before, 5 weeks during, and 8-12 weeks after MPTP/probenecid treatment, the behavioral deficits in gait pattern, spontaneous ambulatory movement, and balance performance were reversed; whereas neuronal loss and impairment in cognitive skill, motor coordination, and amphetamine-stimulated locomotor activity were not altered when compared to the sedentary chronic MPD animals.


CONCLUSIONS
This study indicates that in spite of the drastic loss of dopaminergic neurons and depletion of dopamine in the severe chronic MPD, endurance exercise training effectively reverses the Parkinson's like behavioral deficits related to regular movement, balance and gait performance.
Pothakos
Konstantinos
K
Department of Pharmacological and Pharmaceutical Sciences, University of Houston, Houston, Texas 77204, USA. kpothako@Central.uh.edu
Kurz
Max J
MJ
Lau
Yuen-Sum
YS
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology; D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D001259:Ataxia; D004195:Disease Models, Animal; D005684:Gait / Q000187:drug effects; D020267:MPTP Poisoning / Q000534:rehabilitation*; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D009410:Nerve Degeneration / Q000517:prevention & control* / Q000523:psychology; D010300:Parkinson Disease / Q000209:etiology / Q000534:rehabilitation; D010805:Physical Conditioning, Animal / Q000523:psychology*; D004856:Postural Balance / Q000187:drug effects; D011339:Probenecid / Q000494:pharmacology
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000661:Amphetamine; D011339:Probenecid