Modulation of cellular redox environment as a novel therapeutic strategy for Parkinson's disease

Abstract

Parkinson's disease (PD) is an incurable neurodegenerative movement disorder. PD affects 2% of the population above 65 years old; however, with the growing number of senior citizens, PD prevalence is predicted to increase in the following years. Pathologically, PD is characterized by dopaminergic cell neurodegeneration in the substantia nigra, resulting in decreased dopamine levels in the nigrostriatal pathway, triggering motor symptoms. Although the pathological mechanisms leading to PD are still unclear, large evidence indicates that oxidative stress plays an important role, not only because it increases with age which is the most significant risk factor for PD development, but also as a result of alterations in several processes, particularly mitochondria dysfunction. The modulation of oxidative stress, especially using dietary mitochondriotropic antioxidants, represents a promising approach to prevent or treat PD. Although most mitochondria‐targeted antioxidants with beneficial effects in PD‐associated models have failed to show any therapeutic benefit in clinical trials, several questions remain to be clarified. Hereby, we review the role played by oxidative stress in PD pathogenesis, emphasizing mitochondria as reactive oxygen species (ROS) producers and as targets for oxidative stress‐related dysfunctional mechanisms. In addition, we also describe the importance of using dietary‐based mitochondria‐targeted antioxidants as a valuable strategy to counteract the deleterious effects of ROS in pre‐clinical and/or clinical trials of PD, pointing out their significance to slow, and possibly halt, the progression of PD.

Polyphenols and Small Phenolic Acids as Cellular Metabolic Regulators

“…That said, the medicinal potential of small phenolic acids and the precursor polyphenols, such as curcumin ( Curcuma longa ) and green tea ( Camellia sinensis) , and its catechins can be severely affected by limited systemic and target tissue bioavailability and rate of metabolism. Many of these beneficial compounds only reach the systemic circulation though limited gut absorbance [ 1 , 9 , 11 ]. Nevertheless, the health benefits of polyphenols are related to bioavailability, which depends on the food processing as well as digestion in the gastric intestine and subsequent bacterial metabolism in the gastric intestine and cellular metabolism of these food components.…”

“…Nevertheless, the health benefits of polyphenols are related to bioavailability, which depends on the food processing as well as digestion in the gastric intestine and subsequent bacterial metabolism in the gastric intestine and cellular metabolism of these food components. Data regarding polyphenol absorption and tissue distribution are derived largely from animal studies [ 1 , 9 , 11 ].…”

“…Efforts to modulate, as proof of principle, that oxidative stress and concomitant inflammation, demonstrate modulation of oxidative stress, especially by using dietary mitochondria augmenting antioxidants. This represents a promising approach to prevent or treat diseases, such as Parkinson’s disease and Loue Gehrig’s disease (amyotrophic lateral sclerosis) [ 5 , 9 ]. However, most mitochondria-targeted antioxidants with beneficial effects, in associated models, have often failed to demonstrate clinical therapeutic benefit.…”

“…Any role played by oxidative stress in neurodegeneration, such as Parkinson’s and Alzheimer’s disease pathogenesis, emphasize mitochondria as generators of deleterious reactive oxygen species (ROS) and reactive nitrogen species (RNS), which are both targets for oxidative stress-related pathobiological mechanisms. Polyphenols and phenolic compounds, such as catechins, quercetin and curcuminoids, are actively researched modulators of PD and hold promise in treating or preventing several neurodegenerative diseases [ 9 ].…”

The Role of the NRF2 Pathway in Maintaining and Improving Cognitive Function

“…NRF2 is expressed in all tissue but in recent years attention has turned to its role in the brain and how its activation can be used to elicit neuroprotection and lead to cognitive enhancement [ 28 , 29 ]. Although experimental evidence points to an indisputable role of NRF2 activation in mitigating neurodegeneration and improving cognition, the clinical use of NRF2 activators for treating cognitive impairment related conditions represents an incipient and controversial research topic.…”