Physical activity has been shown to be neuroprotective in lesions affecting the basal ganglia. Using a treadmill exercise paradigm, we investigated the effect of exercise on neurorestoration. The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned mouse model provides a means to investigate the effect of exercise on neurorestoration because 30-40% of nigrostriatal dopaminergic neurons survive MPTP lesioning and may provide a template for neurorestoration to occur. MPTP-lesioned C57 BL/6J mice were administered MPTP (four injections of 20 mg/kg free-base, 2 hr apart) or saline and divided into the following groups: (1). saline; (2). saline + exercise; (3). MPTP; and (4) MPTP + exercise. Mice in exercise groups were run on a motorized treadmill for 30 days starting 4 days after MPTP lesioning (a period after which MPTP-induced cell death is complete). Initially, MPTP-lesioned + exercise mice ran at slower speeds for a shorter amount of time compared to saline + exercise mice. Both velocity and endurance improved in the MPTP + exercise group to near normal levels over the 30-day exercise period. The expression of proteins and genes involved in basal ganglia function including the dopamine transporter (DAT), tyrosine hydroxylase (TH), and the dopamine D1 and D2 receptors, as well as alterations on glutamate immunolabeling were determined. Exercise resulted in a significant downregulation of striatal DAT in the MPTP + exercise compared to MPTP nonexercised mice and to a lesser extent in the saline + exercised mice compared to their no-exercise counterparts. There was no significant difference in TH protein levels between MPTP and MPTP + exercise groups at the end of the study. The expression of striatal dopamine D1 and D2 receptor mRNA transcript was suppressed in the saline + exercise group; however, dopamine D2 transcript expression was increased in the MPTP + exercise mice. Immunoelectron microscopy indicated that treadmill exercise reversed the lesioned-induced increase in nerve terminal glutamate immunolabeling seen after MPTP administration. Our data demonstrates that exercise promotes behavioral recovery in the injured brain by modulating genes and proteins important to basal ganglia function.

Administration of the neurotoxicant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to C57BL/6 mice targets nigrostriatal dopaminergic neurons, leading to cell death and the depletion of striatal dopamine. After MPTP lesioning in young adult mice, surviving nigrostriatal dopaminergic neurons display robust and reproducible return of striatal dopamine weeks to months after injury. Thus, the mouse provides an excellent model with which to investigate the mechanisms underlying neuroplasticity of the nigrostriatal system following neurotoxic injury. The purpose of this study was to analyze proteins and mRNA transcripts of genes involved in dopamine biosynthesis (tyrosine hydroxylase; TH) and uptake (dopamine transporter; DAT) with regard to time course (7-90 days) after MPTP lesioning. Molecular analysis using immunohistochemistry and Western immunoblotting techniques demonstrated an increase in striatal TH by 30-60 days postlesioning that returned to near-control (prelesioned) levels by 60-90 days. In situ hybridization histochemistry indicated that this increase in TH protein might be due in part to increased TH mRNA expression in surviving nigrostriatal dopaminergic neurons. Analysis of TH protein at 7, 30, 60, and 90 days postlesioning with two-dimensional polyacrylamide gel electrophoresis in conjunction with Western immunoblotting revealed altered TH protein isoforms migrating at isoelectric points different from those of the native isoform. In contrast to TH protein, which returned to prelesioned levels by 60 days, DAT protein analysis showed that increased expression of striatal DAT protein did not return to near-prelesion levels until 90 days postlesioning. These results suggest that TH and DAT may differ in their time course of expression in surviving dopaminergic neurons and may play a role in mediating the return of striatal dopamine.

The no observable effect level was greater than six biweekly bilateral 0.50 mg/eye doses or two biweekly bilateral 1.0 mg/eye doses. These pharmacokinetic and safety data support monthly 1 or 2 mg/eye dose regimens in human clinical trials.

The neurotoxicant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) provides an excellent opportunity to study repair and response to injury in the basal ganglia. Administration to mammals leads to the destruction of nigrostriatal dopaminergic neurons and depletion of striatal dopamine. In the squirrel monkey (Saimiri sciureus), MPTP-lesioning results in parkinsonian motor symptoms including bradykinesia, postural instability, and rigidity. Over time animals display motor behavioral recovery. To better understand this mechanism we employed a lesioning regimen of two or six subcutaneous injections of MPTP (2.0 mg/kg, free-base) to generate mild or moderate parkinsonism. Brain tissue was harvested at 6 weeks or 9 months after the last injection and analyzed for dopamine and its metabolites by high performance liquid chromatography (HPLC), and by immunohistochemical staining and Western immunoblotting for the expression of tyrosine hydroxylase (TH), dopamine transporter (DAT), and dopamine- and cAMP-responsive protein phosphatase of 32 kDa (DARPP-32), an effector molecule enriched in striatal medium spiny neurons. Several months after MPTP-lesioning, when squirrel monkeys displayed full motor behavioral recovery, striatal dopamine levels remained low with a greater return in the ventral striatum. This finding is consistent with other reports using neurotoxicant-lesioning models of the basal ganglia in rodents and other species of nonhuman primates. Elevated dopamine turnover ratio and decreased DAT expression appeared in early behavioral recovery at the 6-week time point in both mild- and moderate-parkinsonian monkeys. Tyrosine hydroxylase and DAT expression was increased in late stage recovery even within dopamine-depleted regions and supports sprouting. Altered DARPP-32 expression suggests a role of medium spiny neurons in recovery.

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