title: Intervention with exercise restores motor deficits but not nigrostriatal loss in a progressive MPTP mouse model of Parkinson's disease.
abstract: Many studies have investigated exercise therapy in Parkinson's disease (PD) and have shown benefits in improving motor deficits. However, exercise does not slow down the progression of the disease or induce the revival of lost nigrostriatal neurons. To examine the dichotomy of behavioral improvement without the slowing or recovery of dopaminergic cell or terminal loss, we tested exercise therapy in an intervention paradigm where voluntary running wheels were installed half-way through our progressive PD mouse model. In our model, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is administered over 4 weeks with increased doses each week (8, 16, 24, 32-kg/mg). We found that after 4 weeks of MPTP treatment, mice that volunteered to exercise had behavioral recovery in several measures despite the loss of 73% and 53% tyrosine hydroxylase (TH) within the dorsolateral (DL) striatum and the substantia nigra (SN), respectively which was equivalent to the loss seen in the mice that did not exercise but were also administered MPTP for 4 weeks. Mice treated with 4 weeks of MPTP showed a 41% loss of vesicular monoamine transporter II (VMAT2), a 71% increase in the ratio of glycosylated/non-glycosylated dopamine transporter (DAT), and significant increases in glutamate transporters including VGLUT1, GLT-1, and excitatory amino acid carrier 1. MPTP mice that exercised showed recovery of all these biomarkers back to the levels seen in the vehicle group and showed less inflammation compared to the mice treated with MPTP for 4 weeks. Even though we did not measure tissue dopamine (DA) concentration, our data suggest that exercise does not alleviate motor deficits by sparing nigrostriatal neurons, but perhaps by stabilizing the extraneuronal neurotransmitters, as evident by a recovery of DA and glutamate transporters. However, suppressing inflammation could be another mechanism of this locomotor recovery. Although exercise will not be a successful treatment alone, it could supplement other pharmaceutical approaches to PD therapy.
authors.affiliation: Research Services, VA Medical Center/Portland, Mail Code: RD-29, Research Services, 3710 SW Veterans Hospital Road, Portland, OR 97239, United States.
authors.forename: M D
authors.initials: MD
authors.lastname: Sconce
authors.affiliation: Research Services, VA Medical Center/Portland, Mail Code: RD-29, Research Services, 3710 SW Veterans Hospital Road, Portland, OR 97239, United States.
authors.forename: M J
authors.initials: MJ
authors.lastname: Churchill
authors.affiliation: Research Services, VA Medical Center/Portland, Mail Code: RD-29, Research Services, 3710 SW Veterans Hospital Road, Portland, OR 97239, United States.
authors.forename: R E
authors.initials: RE
authors.lastname: Greene
authors.affiliation: Research Services, VA Medical Center/Portland, Mail Code: RD-29, Research Services, 3710 SW Veterans Hospital Road, Portland, OR 97239, United States; Department of Behavioral Neuroscience, Oregon Health & Science University, 3181 S.W. Sam Jackson Park Road, Portland, Oregon 97239, United States; Department of Pathology, Oregon Health & Science University, 3181 S.W. Sam Jackson Park Road, Portland, Oregon 97239, United States. Electronic address: meshulc@ohsu.edu.
authors.forename: C K
authors.initials: CK
authors.lastname: Meshul
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000008:administration & dosage; D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D004195:Disease Models, Animal; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D027342:Excitatory Amino Acid Transporter 2 / Q000378:metabolism; D050580:Excitatory Amino Acid Transporter 3 / Q000378:metabolism; D005684:Gait / Q000187:drug effects; D018737:Hand Strength; D007249:Inflammation / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D020734:Parkinsonian Disorders / Q000150:complications / Q000378:metabolism* / Q000503:physiopathology*; D010805:Physical Conditioning, Animal; D020127:Recovery of Function; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D050598:Vesicular Glutamate Transport Protein 1 / Q000378:metabolism; D050493:Vesicular Monoamine Transport Proteins / Q000378:metabolism
chemical_list: D050483:Dopamine Plasma Membrane Transport Proteins; D027342:Excitatory Amino Acid Transporter 2; D050580:Excitatory Amino Acid Transporter 3; C493465:Slc17a7 protein, mouse; C493453:Slc18a2 protein, mouse; C493399:Slc1a1 protein, mouse; C493396:Slc1a2 protein, mouse; D050598:Vesicular Glutamate Transport Protein 1; D050493:Vesicular Monoamine Transport Proteins; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D014446:Tyrosine 3-Monooxygenase
keywords: MPTP; Parkinson’s disease; exercise; glutamate transporters; motor behavior; tyrosine hydroxylase