Neuroprotective effects and mechanisms of exercise in a chronic mouse model of Parkinson’s disease with moderate neurodegeneration

Abstract

The protective impact of exercise on neurodegenerative processes has not been confirmed, and the mechanisms underlying the benefit of exercise have not been determined in human Parkinson's disease or in chronic animal disease models. This research examined the long-term neurological, behavioral, and mechanistic consequences of endurance exercise in experimental chronic parkinsonism. We used a chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced mouse model of Parkinson's disease with moderate neurodegeneration and examined the effects of treadmill exercise on movement and balance coordination, changes in dopamine neuron biomarkers, mitochondrial functions, and neurotrophic factor activities in the nigrostriatal system. The exercise results were compared with that of the control and sedentary chronic parkinsonian animals. After 18 weeks of exercise training in the chronic parkinsonian mice, we observed a significant deterrence in the loss of neuronal dopamine-producing cells and other functional indicators. The impaired movement and balance incoordination in the chronic parkinsonian mice were also markedly reduced following exercise. Mechanistic investigations revealed that the neuronal and behavioral recovery produced by exercise in the chronic parkinsonian mice was associated with an improved mitochondrial function and an increase in the brain region-specific levels of brain-derived and glial cell line-derived neurotrophic factors. Our findings indicate that exercise not only produces neuronal and mitochondrial protection, it also boosts nigrostriatal neurotrophic factor levels in the chronic parkinsonian mice with moderate neurodegeneration. Therefore, modifying lifestyle with increased exercise activity would be a non-pharmacological neuroprotective approach for averting neurodegenerative processes, as demonstrated in experimental chronic parkinsonism.

Voluntary running depreciates the requirement of Ca2+-stimulated cAMP signaling in synaptic potentiation and memory formation

“…For instance, physical exercise has been reported to improve vocabulary learning in young and aged humans (Yaffe et al 2001;Winter et al 2007), increase hippocampus size and enhance memory (Erickson et al 2011), and prevent cognitive decline in the elderly (Etnier et al 2007;Deeny et al 2008). Exercise also attenuates defective neuronal functions in animal models of spinocerebellar ataxia type 1 (Fryer et al 2011), Parkinson's disease (Lau et al 2011), and Alzheimer's disease (Adlard et al 2005;Nichol et al 2007). A significant knowledge gap in better understanding the beneficial effects and the underlying mechanism of physical exercise is whether it can exert its effects on defects in specific signaling pathways that regulate synaptic plasticity and memory formation.…”

Melatonin 4 mg as prophylactic therapy for primary headaches: a pilot study

“…Furthermore, the PD patients who underwent treadmill training also showed significant mood and disease course improvements (as measured by the BDI and the UPDRS). Conventionally, exercise is thought to produce an overall benefit in terms of physical fitness and mental stimulation, to slow down the aging process, and to help prevent the onset of chronic disease (Lau et al, 2011;van Praag et al, 2005;Pereira et al, 2007). Furthermore, the impact of exercise in promoting brain angiogenesis and neurogenesis has been well established, supporting the notion that exercise can act to slow decline of cognitive and memory function during the course of normal aging (van Praag et al, 2005;Pereira et al, 2007).…”

“…To date, a wide range of physical therapy modalities has been proposed and employed to treat motor impairment in PD (Ceravolo et al, 2001;Picelli et al, 2012a,b;Carda et al, 2012;Picelli et al, 2013Picelli et al, , 2015Smania et al, 2013;Tomlinson et al, 2013). In particular, the implementation of physical activity programs for people with PD has resulted in improvements in daily activities, motor performance, ambulation and overall functional independence (Lau et al, 2011). Furthermore, in experimental animal models of PD, aerobic exercise has been shown to improve neurochemical and mitochondrial function, with a positive impact on cognitive and emotional aspects of behavior (Pothakos et al, 2009;Pietrelli et al, 2012;Tuon et al, 2012Tuon et al, , 2014 Cognitive-motor relationships have been explored in patients with PD (Domellöf et al, 2011;Poletti et al, 2012).…”

GDNF and PD: Less Common Points of View

“…Recently, daily treadmill exercise similar to clinical settings (30 min/day, 5 days/week for 4 weeks) was shown to up-regulate both GDNF and BDNF in the lesioned and intact sides of the striatum (Tajiri et al, 2010). In a chronic MPTP mouse model with moderate neurodegeneration treadmill exercise during 18 weeks drastically increased GDNF levels in the striatum but not in the substantia nigra, and the opposite was observed for BDNF (Lau et al, 2011). The improvement of motor function observed in many studies of forced limb use, treadmill running or running-wheel exercise in both 6-OHDA (Mabandla et al, 2004;Tillerson et al, 2001;2003;Yoon et al, 2007) and MPTP (Fisher et al, 2004;Tillerson et al, 2003) models of PD raised the hypothesis that upregulation of GDNF might mediate, or at least contribute to, the protection of the nigrostriatal pathway observed in those reports (A.D. .…”