Exercise-Induced Neuroprotection and Recovery of Motor Function in Animal Models of Parkinson's Disease

Abstract

Parkinson's disease (PD) is manifested by progressive motor, autonomic, and cognitive disturbances. Dopamine (DA) synthesizing neurons in the substantia nigra (SN) degenerate, causing a decline in DA level in the striatum that leads to the characteristic movement disorders. A disease-modifying therapy to arrest PD progression remains unattainable with current pharmacotherapies, most of which cause severe side effects and lose their efficacy with time. For this reason, there is a need to seek new therapies supporting the pharmacological treatment of PD. Motor therapy is recommended for pharmacologically treated PD patients as it alleviates the symptoms. Molecular mechanisms behind the beneficial effects of motor therapy are unknown, nor is it known whether such therapy may be neuroprotective in PD patients. Due to obvious limitations, human studies are unlikely to answer these questions; therefore, the use of animal models of PD seems indispensable. Motor therapy in animal models of PD characterized by the loss of dopaminergic neurons has neuroprotective and neuroregenerative effects, and the completeness of neuronal protection may depend on (i) degree of neuronal loss, (ii) duration and intensity of exercise, and (iii) time elapsed between insult and commencing of training. As the physical activity is neuroprotective for dopaminergic neurons, the question arises what is the mechanism of this protective action. A current hypothesis assumes a central role of neurotrophic factors in the neuroprotection of dopaminergic neurons, even though it is still not clear whether increased DA level in the nigrostriatal axis results from neurogenesis of dopaminergic neurons in the SN, recovery of the phenotype of dopaminergic neurons, increased sprouting of the residual dopaminergic axons in the striatum, or generation of local striatal neurons from inhibitory interneurons. In the present review, we discuss studies describing the influence of physical exercise on the PD-like changes manifested in animal models of the disease and focus our interest on the current state of knowledge on the mechanism of neuroprotection induced by physical activity as a supportive therapy in PD.

BDNF as a Promising Therapeutic Agent in Parkinson’s Disease

“…Tuon et al [131] reported an attenuated decline of proBDNF content in 6-OHDA-induced PD rats trained for 60 days before lesion. In our study, we also noted a higher BDNF and GDNF immunostaining intensity in nigrostriatal areas of MPTP-treated mice which started treadmill training before (preceding training) and after (follow-up training) intoxication, as compared to control groups both sedentary and exercised [125]. Similarly, enzyme-linked immunosorbent assay showed a significant increase in BDNF in both MPTP preceding training and follow-up training groups as compared to both controls and MPTP sedentary group in the midbrain including SN.…”

“…All these substances are the markers of the dopaminergic system and drop in the course of PD [135][136][137]. Furthermore, our study revealed a recovery of the intensity of vesicular monoamine transporter 2 (VMAT2) immunostaining in SN in exercised MPTP mice, indicative of the increase in the number of dopaminergic neurons [125].…”

“…BDNF production was shown to be stimulated by both voluntary [75] and forced physical activity [125][126][127][128][129][130][131][132][133]. BDNF upregulation was observed in midbrain [125], SN [126,128,129], ST [127,129,131,133], hippocampus [133], and cortex [132,133]. Tuon et al [131] reported an attenuated decline of proBDNF content in 6-OHDA-induced PD rats trained for 60 days before lesion.…”

“…BDNF brain level increase due to exercise was accompanied by several other effects. In animal models of PD, exercise was able to increase the number of TH-ir neurons in SN [125][126][127][128][129][130]134], the TH protein level in SN [126,128] and ST [128,134], and TH-ir fiber intensity in ST [127,128]. Physical activity also led to a normalization of the DA content in SN and/or ST [75,126,129,130,132,133] and of 3,4-dihydroxyphenylacetic acid (DOPAC) level in ST [129,133], to a slight increase in the homovanillic acid (HVA) content in ST [133] and an elevation in the DAT level in ST [126,133].…”

Environmental Enrichment Attenuates Oxidative Stress and Alters Detoxifying Enzymes in an A53T α-Synuclein Transgenic Mouse Model of Parkinson’s Disease

“…Both clinical and experimental evidence of the impact of physical exercise on PD are increasing, whereby exercise has been found to induce various neuroprotection mechanisms [ 27 , 28 ]. Physical activity not only improves motor function, but also enhances non-motor symptoms and cognitive function in PD [ 29 , 30 ].…”