Studies have suggested that there are beneficial effects of exercise in patients with Parkinson's disease, but the underlying molecular mechanisms responsible for these effects are poorly understood. Studies in rodent models provide a means to examine the effects of exercise on dopaminergic neurotransmission. Using intensive treadmill exercise, we determined changes in striatal dopamine in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned mouse. C57BL/6J mice were divided into four groups: (1) saline, (2) saline plus exercise, (3) MPTP, and (4) MPTP plus exercise. Exercise was started 5 d after MPTP lesioning and continued for 28 d. Treadmill running improved motor velocity in both exercise groups. All exercised animals also showed increased latency to fall (improved balance) using the accelerating rotarod compared with nonexercised mice. Using HPLC, we found no difference in striatal dopamine tissue levels between MPTP plus exercise compared with MPTP mice. There was an increase detected in saline plus exercise mice. Analyses using fast-scan cyclic voltammetry showed increased stimulus-evoked release and a decrease in decay of dopamine in the dorsal striatum of MPTP plus exercise mice only. Immunohistochemical staining analysis of striatal tyrosine hydroxylase and dopamine transporter proteins showed decreased expression in MPTP plus exercise mice compared with MPTP mice. There were no differences in mRNA transcript expression in midbrain dopaminergic neurons between these two groups. However, there was diminished transcript expression in saline plus exercise compared with saline mice. Our findings suggest that the benefits of treadmill exercise on motor performance may be accompanied by changes in dopaminergic neurotransmission that are different in the injured (MPTP-lesioned) compared with the noninjured (saline) nigrostriatal system.
IMPORTANCE Convergent biological, epidemiological, and clinical data identified urate elevation as a candidate strategy for slowing disability progression in Parkinson disease (PD).OBJECTIVE To determine the safety, tolerability, and urate-elevating capability of the urate precursor inosine in early PD and to assess its suitability and potential design features for a disease-modification trial. DESIGN, SETTING, AND PARTICIPANTSThe Safety of Urate Elevation in PD (SURE-PD) study, a randomized, double-blind, placebo-controlled, dose-ranging trial of inosine, enrolled participants from 2009 to 2011 and followed them for up to 25 months at outpatient visits to 17 credentialed clinical study sites of the Parkinson Study Group across the United States. Seventy-five consenting adults (mean age, 62 years; 55% women) with early PD not yet requiring symptomatic treatment and a serum urate concentration less than 6 mg/dL (the approximate population median) were enrolled.INTERVENTIONS Participants were randomized to 1 of 3 treatment arms: placebo or inosine titrated to produce mild (6.1-7.0 mg/dL) or moderate (7.1-8.0 mg/dL) serum urate elevation using 500-mg capsules taken orally up to 2 capsules 3 times per day. They were followed for up to 24 months (median, 18 months) while receiving the study drug plus 1 washout month. MAIN OUTCOMES AND MEASURESThe prespecified primary outcomes were absence of unacceptable serious adverse events (safety), continued treatment without adverse event requiring dose reduction (tolerability), and elevation of urate assessed serially in serum and once (at 3 months) in cerebrospinal fluid.RESULTS Serious adverse events (17), including infrequent cardiovascular events, occurred at the same or lower rates in the inosine groups relative to placebo. No participant developed gout and 3 receiving inosine developed symptomatic urolithiasis. Treatment was tolerated by 95% of participants at 6 months, and no participant withdrew because of an adverse event. Serum urate rose by 2.3 and 3.0 mg/dL in the 2 inosine groups (P < .001 for each) vs placebo, and cerebrospinal fluid urate level was greater in both inosine groups (P = .006 and <.001, respectively). Secondary analyses demonstrated nonfutility of inosine treatment for slowing disability.CONCLUSIONS AND RELEVANCE Inosine was generally safe, tolerable, and effective in raising serum and cerebrospinal fluid urate levels in early PD. The findings support advancing to more definitive development of inosine as a potential disease-modifying therapy for PD. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00833690
The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned mouse serves as a model of basal ganglia injury and Parkinson’s disease. The present study investigated the effects of MPTP-induced lesioning on associative memory, conditioned fear, and affective behavior. Male C57BL/6 mice were administered saline or MPTP and separate groups were evaluated at either 7 or 30 days post-lesioning. In the social transmission of food preference test, mice showed a significant decrease in preference for familiar food 30 days post-MPTP compared to controls. Mice at both 7 and 30 days post-MPTP-lesioning had increased fear extinction compared to controls. HPLC analysis of tissues homogenates showed dopamine and serotonin were depleted in the striatum, frontal cortex, and amygdala. No changes in anxiety or depression were detected by the tail suspension, sucrose preference, light-dark preference, or hole-board tests. In conclusion, acute MPTP-lesioning regimen in mice causes impairments in associative memory and conditioned fear, no mood changes, and depletion of dopamine and serotonin throughout the brain.
Background Adenosine A2A receptor antagonists reduce or prevent the development of dyskinesia in animal models of levodopa-induced dyskinesia. Methods We examined the association between self-reported intake of the A2A receptor antagonist caffeine and time to dyskinesia in the Comparison of the Agonist Pramipexole with Levodopa on Motor Complications of Parkinson’s Disease (CALM-PD) and CALM Cohort extension studies, using a Cox proportional hazards model adjusting for age, baseline Parkinson’s severity, site, and initial treatment with pramipexole or levodopa. Results For subjects who consumed > 12 ounces of coffee/day, the adjusted hazard ratio for the development of dyskinesia was 0.61 (95% confidence interval, 0.37–1.01) compared to subjects who consumed < 4 ounces/day. For subjects who consumed between 4 and 12 ounces/day, the adjusted hazard ratio was 0.73 (C.I. 0.46–1.15) (test for trend, p = 0.05). Conclusions These results support the possibility that caffeine may reduce the likelihood of developing dyskinesia.
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