Exploring the Biological Basis for Exercise Neuroprotection in Parkinson's Disease

Parkinson's disease (PD) is the second most common neurodegenerative disease, affecting an estimated 4 million individuals and 1% of those over the age of 60. The pathologic hallmark of PD are Lewy bodies in neurons and these inclusion bodies are largely made up of misfolded α-synuclein. These α-synuclein inclusion bodies cause mitochondrial respiratory dysfunction which results in reactive oxygen species causing oxidative stress; this, in turn, leads to more aggregation of α-synuclein and a vicious cycle ensues. Ultimately, this vicious cycle results in dopaminergic neuron cell death causing a decrease in dopamine in the nigrostriatal pathway. Mitochondrial dysfunction and subsequent oxidative stress are also caused by environmental toxins (e.g., trichloroethylene, paraquat) and neuroinflammation, both of which are theorized to play a prominent role in PD pathology. Because of this, neuroprotective strategies in PD have focused on limiting exposure to environmental toxins and, more importantly, decreasing pro-inflammatory mechanisms.

Evidence has been accumulating that exercise improves symptoms and quality of life and is neuroprotective in PD. In one meta-analysis, they found that regular exercise delays the progression of PD motor symptoms, mobility, and balance deterioration. Another meta-analysis reported a reduced risk for developing PD in the pre-clinical phase for those performing moderate to vigorous exercise. Another meta-analysis showed a 40% risk reduction in developing PD for people regularly performing moderate to vigorous activity aged 35-39 or within the previous ten years. Based on these findings, it can be reasonably deduced that moderate to vigorous exercise prior to PD diagnosis is neuroprotective. Moreover, exercise may also slow the progression of degeneration after PD diagnosis.

A prominent theory underlying neuroprotection in PD is that exercise may mitigate the pro-inflammatory milieu thereby protecting and slowing the progressive loss of dopaminergic neurons. Various chemical mediators, antioxidant agents, and cytokines have been shown to play a role in the development, progression, and severity of PD, including interleukin 6 (IL-6) and 10 (IL-10), tumor necrosis factor (TNF), and the interferon gamma family (IFNγ). Some of these chemicals are anti-inflammatory and some are pro-inflammatory. While these are some of the most commonly studied cytokines, there are many others that are understudied in PD and they may also contribute to the internal state of inflammation in PD. Therefore, it is important to examine the collective blend of these cytokines and chemokines to understand the inflammatory milieu in PD as a result of acute and chronic exercise. While regular exercise may be neuroprotective in PD by reducing oxidative stress, the release of antioxidant enzymes via exercise (superoxide dismutase (SOD), glutathione peroxidase, catalase) may also contribute to an overall decrease in the state of inflammation in PD.

Another group of compounds theorized to play a role in the mitigation of PD progression are the neurotrophins (e.g., brain-derived neurotrophic factor (BDNF), vascular endothelial growth factor (VEGF), glial cell line-derived neurotrophic factor (GDNF)). All three of the aforementioned neurotrophins are activity-dependent meaning they increase as a result of exercise. GDNF and BDNF have received the most attention and are theorized to aid in neuroregeneration and neuroprotection in PD by protecting dopaminergic neurons. There are decreased levels of BDNF in the dopaminergic nigrostriatal pathways in people with PD (PwP). A reduction in the bioavailability of dopamine compounded by a decrease in BDNF has been shown to be associated with PD signs (movement dysfunction, resting tremor, and bradykinesia). Additionally, BDNF may also be related to an anti-inflammatory milieu in PD thereby highlighting the need to investigate the cytokines and neurotrophins together. Lastly, VEGF may indirectly impact neuroprotection in PD by improving blood supply (angiogenesis) and synaptic activity.

Thus, there are three possible mechanisms that are theorized to underlie the disease modifying effects of exercise in PD: decreasing the inflammatory milieu via cytokines, decreasing the inflammatory milieu via antioxidant enzymes, and improved neuroprotection of neurons via neurotrophins. Currently, it is not understood if one of these methods predominates or if it is the combination of these mechanisms that underlie neuroprotection. Theoretically, all three mechanisms may slow the progression of PD by breaking up the vicious cycle of α-synuclein aggregation, mitochondrial toxicity, and oxidative stress. These purported mechanisms warrant further research attention. Importantly, there are no studies to our knowledge that have looked at all three mechanisms together in one study. Since there are interrelationships among the three mechanisms it makes sense to explore these in more detail. Importantly, it is not known how these mechanisms respond to different doses of exercise. Therefore, this study will examine the relationship of exercise dose to these mechanisms to gain greater insight into neuroprotection in PD. The following are the specific aims of this study: