Delayed Exercise-Induced Functional and Neurochemical Partial Restoration Following MPTP

Abstract

In two experiments, MPTP was administered to C57/BL6 mice according to a single-dose weekly regime (MPTP: 1 × 30 mg/kg on the fifth day of the week, Friday, over 4 weeks) with vehicle group (Vehicle: 1 × 5 ml/kg) treated concurrently. Exercise schedules (delayed) were introduced either at the beginning of the week after the second MPTP injection (MPTP + Exercise(2) group), or at the beginning of the week after the fourth MPTP injection (MPTP + Exercise(4) group). Wheel-running was provided on the first 4 days of each week (Monday-Thursday) more than 30-min periods. In Experiment I, wheel-running exercise was introduced either after 2 or 4 weeks after MPTP/Vehicle. MPTP and Vehicle groups not provided access to the running wheels were placed in single cages within the wheel-running room over 30-min concomitantly with the wheel-running groups. In Experiment II, wheel-running exercise was introduced 2 weeks after MPTP/Vehicle but a no-exercise control group with non-revolving wheel included (MPTP-Wheel). In both experiments, spontaneous motor activity tests during 60-min intervals were performed at the end (Fridays) of weeks 1, 2, 3, 4, 6, 8, and 10, where the week on which the first injection of MPTP was the first week; in the case of weeks 1-4, this was immediately before MPTP/Vehicle injections. It was observed that the introduction of the exercise schedule after the second MPTP injection, but not after the fourth injection, restored motor activity that had been markedly elevated by the end of the tenth week. Subthreshold administration of L-dopa tests was performed after the spontaneous motor activity tests 6, 8 and 10; these indicated significant effects of exercise, MPTP + Exercise(2) group, on Tests 6 and 8, but not Test 10. The physical exercise schedule in that group also showed markedly attenuated loss of dopamine (DA). Restoration of MPTP-induced motor activity deficits and DA loss was a function of the point at which exercise was introduced, in the present case after two administrations of the neurotoxin. In Experiment II, physical exercise markedly attenuated the hypokinesic effect of MPTP in the exercise condition, MPTP-exercise, but not in the non-exercise conditions, MPTP-Cage and MPTP-Wheel, for both spontaneous motor activity and L-dopa-induced activity. MPTP-induced loss of DA was also attenuated by exercise.

Restoration of MPTP-induced deficits by exercise and Milmed®co-treatment

“…The results showed that wheel-running exercise (30-min sessions, 4 days/week) combined with the treated yeast Milmed ® suspension (administered 4 times/week), the MPTP + Exercise + Yeast (MC) [MPTP + Exercise + Milmed ® (MC)] group, restored spontaneous motor activity markedly by test day 10, restored completely subthreshold L-Dopa-induced activity, and dopamine concentration to 76% of control values, in the condition wherein two administrations of MPTP (2 × 40 mg/kg) were given prior to initiation of exercise and/or Milmed ® treatment. Physical exercise by itself, MPTP + Exercise (MC) group, attenuated these deficits only partially, as has been observed several times previously (Archer & Fredriksson, 2010; Archer & Fredriksson, 2012; Archer & Fredriksson, 2013a; Archer & Fredriksson, 2013b; Archer & Fredriksson, 2013c; Fredriksson et al, 2011). Administration of 4 injections of MPTP each week (4 × 40 mg/kg) induced deficits that were far too severe for amelioration by exercise and Milmed ® : i.e., groups MPTP + Exercise (SC) and MPTP + Exercise + Yeast (SC) whereas the MPTP group received no exercise access.…”

“…Throughout the published series of experiments (Archer & Fredriksson, 2010; Archer & Fredriksson, 2012; Archer & Fredriksson, 2013a; Archer & Fredriksson, 2013b; Archer & Fredriksson, 2013c; Fredriksson et al, 2011) and (T Archer, 2014, unpublished data), applying different MPTP dose regimes and number of administrations, the percentage increase in striatal dopamine levels, following the exercise invention, has varied as follows: 15% (5 weeks of exercise), 47% (14 weeks of exercise), 44% (7 weeks of exercise), 21% (14 weeks of exercise), 20% (10 weeks of exercise), 42% (14 weeks of exercise), 27% (10 weeks of exercise) and in the present experiment 20% (10 weeks of exercise). Despite this consistent evidence that running-wheel exercise induced reliable elevations in striatal dopamine concentration, it is obvious that exercise by itself was not sufficient to ensure complete restoration.…”

“…The identical procedure to that employed previously (Archer & Fredriksson, 2012) was maintained. Access to the running wheel was presented on the 1st four days of the week (Mon.–Thurs.)…”

“…Although physical exercise by itself ameliorates functional, motor activity, and neurochemical, dopamine, deficits induced by the selective dopamine neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, Archer & Fredriksson, 2010; Archer & Fredriksson, 2012; Archer & Fredriksson, 2013a; Archer & Fredriksson, 2013b; Archer & Fredriksson, 2013c; Fredriksson et al, 2011), the combination of physical exercise with Milmed ® provided evidence of complete restoration of these deficits (Archer & Fredriksson, 2013a). The efficacy of physical exercise (Archer, 2011; Archer, Johansson & Fredriksson, 2011; Earhart & Falvo, 2013) and physiotherapy (Cholewa, Boczarska-Jedynak & Opala, 2013) for Parkinsonism and other neurodegenerative conditions has been well-documented with ever-increasing evidence from both clinical and laboratory studies (Park et al, 2014; Wang et al, 2013; Zigmond & Smeyne, 2014).…”

Effects of Physical Exercise on Depressive Symptoms and Biomarkers in Depression

“…(ix) Both the psychomotor retardation and anhedonia symptom profiles associated with deficits in dopaminergic systems; it has been shown that physical exercise ameliorates both functional, biomarker and quality-of-life aspects (34,35,36). (x) Finally, although physical exercise assumes no direct side-effects compared with traditional antidepressant medication, there exist real risks that individuals with depressive tendencies undergoing depressive episodes may 'abuse' varieties of exercise for the purpose of mood-elevation (37).…”