Abstract
Neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS), currently affect more than 6 million people in the United States. Unfortunately, there are no treatments that slow or prevent disease development and progression. Regardless of the underlying cause of the disorder, age is the strongest risk factor for developing these maladies, suggesting that changes that occur in the aging brain put it at increased risk for neurodegenerative disease development. Moreover, since there are a number of different changes that occur in the aging brain, it is unlikely that targeting a single change is going to be effective for disease treatment. Thus, compounds that have multiple biological activities that can impact the various age-associated changes in the brain that contribute to neurodegenerative disease development and progression are needed. The plant-derived flavonoids have a wide range of activities that could make them particularly effective for blocking the age-associated toxicity pathways associated with neurodegenerative diseases. In this review, the evidence for beneficial effects of multiple flavonoids in models of AD, PD, HD, and ALS is presented and common mechanisms of action are identified. Overall, the preclinical data strongly support further investigation of specific flavonoids for the treatment of neurodegenerative diseases.
Highlights
What Is Neurodegeneration?Before reviewing the potential beneficial effects of natural products, and in the case of this review, flavonoids, on neurodegeneration, it is essential that a definition of neurodegeneration be established
Among the pathophysiological changes that occur in the aging brain, those that have been identified as potentially contributing to neurodegeneration include increases in oxidative stress, alterations in energy metabolism, loss of neurotrophic support, alterations in protein processing leading to the accumulation of protein aggregates, dysfunction of the neurovascular system, and immune system activation [7,8]
While many flavonoids have only been tested in models of one neurodegenerative disease, others, such as fisetin and 7,8-DHF, have shown efficacy in models of all four of the diseases highlighted in this review
Summary
Before reviewing the potential beneficial effects of natural products, and in the case of this review, flavonoids, on neurodegeneration, it is essential that a definition of neurodegeneration be established. Over 15 years ago, Przedborski et al [1] published a comprehensive discussion of this topic that is still highly relevant today They defined neurodegeneration generally as “any pathological condition primarily affecting neurons”. They characterized neurodegenerative diseases as a large, heterogeneous group of neurological disorders that affect distinct subsets of neurons in specific anatomical locations. They noted that a number of disorders that are either not primary neuronal diseases or where neurons die of a known cause, such as hypoxia or poison, are not neurodegenerative diseases. This suggests that changes that occur in the aging brain put it at increased risk for the development of a neurodegenerative disease and that the identification of those changes could provide a means to develop therapeutics that can at least slow, if not prevent, disease development and/or progression
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