Physical Activity on Neuroinflammation in Parkinson's Disease

Parkinson's Disease (PD) is a chronic progressive neurodegenerative disorder clinically defined by the association of resting tremor, rigidity, bradykinesia, and postural instability. The histopathology of PD is characterized by the loss of neurons in the substantia nigra pars compacta (SNPc) and the accumulation of α-synuclein aggregates within Lewy bodies. The pathogenic mechanisms underlying the development of the disease, however, are not yet fully understood: genetics, cellular oxidative stress, mitochondrial dysfunction, environmental factors, and neuroinflammation are all potential mechanisms involved in the pathogenesis of PD. Several studies have now established the involvement of neuroinflammation in the pathogenesis of PD. It is known that α-synuclein aggregates stimulate microglia and astroglia to secrete pro-inflammatory mediators such as IL 1β, IL6, and TNFα. These molecules activate an inflammatory response characterized by altered blood-brain barrier permeability, leukocyte recruitment, and the expression of other pro-inflammatory cytokines. These events contribute to exposing neurons to oxidative stress and cellular damage. Additionally, cellular damage induces neurons to stimulate the release of DAMPs (Damage Associated Molecular Patterns), which in turn activate glial cells. This creates a state of chronic inflammation that could play a role in the progression of the disease. Supporting this hypothesis, elevated levels of IL1β, IL6, and TNFα have been found in the striatum and SNPc of post-mortem PD samples. The transcription factor Nrf2 is one of the main regulators of cellular protection in response to stress (inflammation, redox, xenobiotics). Nrf2 promotes the expression of several genes that cooperate in a cytoprotective response, which includes antioxidant defense, resolution of inflammation, increased mitochondrial activity, and protein turnover. Recent clinical studies seem to confirm the hypothesis that Nrf2 plays a role in the pathogen