Flavonoids: Potential Candidates for the Treatment of Neurodegenerative Disorders

Abstract

Neurodegenerative disorders, such as Parkinson's disease (PD), Alzheimer's disease (AD), Amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD), are the most concerning disorders due to the lack of effective therapy and dramatic rise in affected cases. Although these disorders have diverse clinical manifestations, they all share a common cellular stress response. These cellular stress responses including neuroinflammation, oxidative stress, proteotoxicity, and endoplasmic reticulum (ER)-stress, which combats with stress conditions. Environmental stress/toxicity weakened the cellular stress response which results in cell damage. Small molecules, such as flavonoids, could reduce cellular stress and have gained much attention in recent years. Evidence has shown the potential use of flavonoids in several ways, such as antioxidants, anti-inflammatory, and anti-apoptotic, yet their mechanism is still elusive. This review provides an insight into the potential role of flavonoids against cellular stress response that prevent the pathogenesis of neurodegenerative disorders.

Keywords: ER stress proteotoxicity; cellular stress response; flavonoids; neurodegenerative disorders; neuroinflammation; oxidative stress.

Figure 1

Role of flavonoids in prevention against cellular stress response. Exposure to stress conditions leads to the activation of cellular stress responses, such as UPR, ER stress, oxidative stress, proteotoxicity, and neuroinflammation. When cells are exposed to any stress condition, it affects the cellular proteome, thus inducing the UPR in the ER and further activation of ER stress. Stress conditions also initiate proteotoxicity by affecting the proteins’ structure, as well as proteasome subunits of the proteasomal degradation machinery, causing the release of misfolded/aggregated proteins in the cytosol, thus inducing proteotoxicity. The release of ROS from mitochondria leads to the generation of oxidative stress. All these cellular stress responses try to eliminate the stress-induced toxicity, but extreme cellular stress responses may lead to cell death. During stress exposure, microglia start to release neuroinflammatory mediators thus causing neuroinflammation. This inflammation creates a hostile environment within the cell and under harsh conditions, leads to cell death. Flavonoids have the potential to combat and prevent these exaggerated cellular stress responses in-turn preventing cell death. ER: Endoplasmic reticulum, ROS: Reactive oxygen species, UPR: Unfolded protein response.