Nutraceutical Antioxidants as Novel Neuroprotective Agents
A variety of antioxidant compounds derived from natural products (nutraceuticals) have demonstrated neuroprotective activity in either in vitro or in vivo models of neuronal cell death or neurodegeneration, respectively. These natural antioxidants fall into several distinct groups based on their chemical structures: (1) flavonoid polyphenols like epigallocatechin 3-gallate (EGCG) from green tea and quercetin from apples; (2) non-flavonoid polyphenols such as curcumin from tumeric and resveratrol from grapes; (3) phenolic acids or phenolic diterpenes such as rosmarinic acid or carnosic acid, respectively, both from rosemary; and (4) organosulfur compounds including the isothiocyanate, L-sulforaphane, from broccoli and the thiosulfonate allicin, from garlic.
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All of these compounds are generally considered to be antioxidants. They may be classified this way either because they directly scavenge free radicals or they indirectly increase endogenous cellular antioxidant defenses, for example, via activation of the nuclear factor erythroid-derived 2-related factor 2 (Nrf2) transcription factor pathway.
Alternative mechanisms of action have also been suggested for the neuroprotective effects of these compounds such as modulation of signal transduction cascades or effects on gene expression. Here, we review the literature pertaining to these various classes of nutraceutical antioxidants and discuss their potential therapeutic value in neurodegenerative diseases.
There are a wide variety of neurodegenerative diseases with distinct symptoms and pathologies. For many of these diseases, the vast majority of cases are sporadic and therefore, the challenge is to discover the underlying causes of neurodegeneration in order to prevent or slow these disorders. Oxidative stress is recognized as a common factor in many neurodegenerative diseases and is a proposed mechanism for age-related degenerative processes as a whole. Numerous studies have provided compelling evidence linking neuronal oxidative stress to Parkinson’s disease (PD), Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS), to highlight but a few.
Oxidative stress occurs when reactive oxygen species (ROS) accumulate in the cell, either from excessive production or insufficient neutralization, causing damage to DNA, lipids, and proteins. Mitochondria are both a major source and target for ROS. Mitochondria are the powerhouses of the cell; they have the essential function of generating cellular energy in the form of ATP. Without ATP the cell will become energy deprived and eventually die. The most effective way for a cell to produce ATP is through oxidative phosphorylation within the mitochondria via the electron transport chain (ETC). The ETC is not entirely efficient so there is a basal level of electron leak under even the most
optimum of conditions.
The inadvertent leakage of electrons and their reaction with molecular oxygen are major contributors to the production of cellular ROS. Moreover, ROS produced within mitochondria subsequently target the various components of the ETC (in particular, complexes I and III), resulting in a vicious feed forward cycle of enhanced generation of ROS, more severe ATP depletion, and ultimately cell death. Various genetic mutations and environmental exposures can undoubtedly sensitize neurons to mitochondrial ROS production either by increasing the exogenous production of free radicals or decreasing endogenous antioxidant defense systems.
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