Fisetin as a Senotherapeutic Agent: Biopharmaceutical Properties and Crosstalk between Cell Senescence and Neuroprotection

Abstract

Like other organs, brain functions diminish with age. Furthermore, for a variety of neurological disorders-including Alzheimer's disease-age is one of the higher-risk factors. Since in many Western countries the average age is increasing, determining approaches for decreasing the effects of aging on brain function is taking on a new urgency. Neuroinflammation and oxidative stress are two convoluted key factors in brain aging and chronic neurodegenerative diseases. The diverseness of factors, causing an age-related decrease in brain functions, requires identifying small molecules that have multiple biological activities that can affect all these factors. One great source of these small molecules is related to polyphenolic flavonoids. Recently, 3,3',4',7-tetrahydroxyflavone (fisetin) has been reported as a potent senotherapeutic capable of extending lifespan by reducing peroxidation levels and enhancing antioxidant cell responses. The neuroprotective effects of fisetin have been shown in several in vitro and in vivo models of neurological disorders due to its actions on multiple pathways associated with different neurological disorders. The present work aims to collect the most recent achievements related to the antioxidant and neuroprotective effects of fisetin. Moreover, in silico pharmacokinetics, pharmacodynamics, and toxicity of fisetin are also comprehensively described along with emerging novel drug delivery strategies for the amelioration of this flavonol bioavailability and chemical stability.

Keywords: fisetin; in silico evaluation; neuroinflammation; neuroprotection; senescence; senolytic drug.

Figure 1

Mechanisms of neuroinflammation. IL-6: interleukin-6; IL-18: interleukin-18; IL-1β: interleukin-1β; TNFα: tumor necrosis factor α; CRP: C-reactive protein; CCL2: C-C motif chemokine ligand 2; NLRP3: NOD-like receptor protein 3.