Exercise-Induced Neuroprotection of the Nigrostriatal Dopamine System in Parkinson's Disease

Abstract

Epidemiological studies indicate that physical activity and exercise may reduce the risk of developing Parkinson's disease (PD), and clinical observations suggest that physical exercise can reduce the motor symptoms in PD patients. In experimental animals, a profound observation is that exercise of appropriate timing, duration, and intensity can reduce toxin-induced lesion of the nigrostriatal dopamine (DA) system in animal PD models, although negative results have also been reported, potentially due to inappropriate timing and intensity of the exercise regimen. Exercise may also minimize DA denervation-induced medium spiny neuron (MSN) dendritic atrophy and other abnormalities such as enlarged corticostriatal synapse and abnormal MSN excitability and spiking activity. Taken together, epidemiological studies, clinical observations, and animal research indicate that appropriately dosed physical activity and exercise may not only reduce the risk of developing PD in vulnerable populations but also benefit PD patients by potentially protecting the residual DA neurons or directly restoring the dysfunctional cortico-basal ganglia motor control circuit, and these benefits may be mediated by exercise-triggered production of endogenous neuroprotective molecules such as neurotrophic factors. Thus, exercise is a universally available, side effect-free medicine that should be prescribed to vulnerable populations as a preventive measure and to PD patients as a component of treatment. Future research needs to establish standardized exercise protocols that can reliably induce DA neuron protection, enabling the delineation of the underlying cellular and molecular mechanisms that in turn can maximize exercise-induced neuroprotection and neurorestoration in animal PD models and eventually in PD patients.

Keywords: basal ganglia; dendritic spine; dopamine; glutamate; medium spiny neuron; neuroprotection; neurotrophic factor; physical activity.

Figure 1

Diagram illustrating that PD has a long presymptomatic period and that exercise may reduce PD risk, delay the appearance of the symptoms, and slow the disease progression. ? indicates that the illustrated possibilities are suggested by indirect evidence but direct evidence is lacking. The diagram is based on Kish et al. (1988), Hornykiewicz (2001), Braak et al. (2004), Gaig and Tolosa (2009), Hawkes et al. (2010), Savica et al. (2010), Coelho and Ferreira (2012), Burke and O'Malley (2013), Goedert et al. (2013), Kordower et al. (2013), Del Tredici and Braak (2016), Noyce et al. (2016) and Salat et al. (2016). The curves and values are approximate because published data are incomplete and variable. Original illustration of Fu-Ming Zhou.

Figure 2

(A) Diagram of the nigrostriatal system and the basal ganglia circuitry of the human brain. From Zhou et al. (2003) with permission. (B) Photograph of a monkey brain coronal section showing the intense DA innervation in the striatum (the putamen and the caudate nucleus) indicated by DAT immunostain. Modified from Lewis et al. (2001) with permission.

Figure 3

Exercise-induced neuroprotection of DA neurons in the SNc and DA axon terminals in the striatum. (A) TH immunostain showing DA axonal innervation under the four conditions. (B) TH immunostain showing DA neurons in the substantia nigra under the four conditions. Scale bar in (B4): 0.1 mm for (A) and 0.05 mm for (B). Modified from Shi et al. (2017) with permission.

Figure 4

Exercise protects MSN dendritic spines. (A) Example dendritic spines under the four conditions. Scale bar, 5 μm. (B) Quantification of dendritic spines under the four conditions. Modified from Chen et al. (2015a) with permission.

Figure 5

Summary diagram showing that exercise triggers trophic factor production that in turn induce neuroprotection and neurorestoration. IT, intratelencephalically projecting cortical neurons; PT, pyramidal tract projecting cortical neurons. Original artwork of Fu-Ming Zhou.