Flavonoid-based therapies in the early management of neurodegenerative diseases

Abstract

During the past several years, there has been enormous progress in the understanding of the causative factors that initiate neuronal damage in various neurodegenerative diseases, including Alzheimer disease, Parkinson disease, multiple sclerosis, amyotrophic lateral sclerosis, and Huntington disease. Preventing neuronal damage and neuronal death will have a huge clinical benefit. However, despite major advances in causative factors that trigger these neurodegenerative diseases, to date there have been no therapies available that benefit patients who suffer from these diseases. Because most neurodegenerative diseases are late-onset and remain asymptomatic for most of the phases, the therapies initiated in advanced stages of the disease have limited value to patients. It may be possible to prevent or halt the disease progression to a great extent if therapies start at the initial stage of the disease. Such therapies may restore neuronal function by reducing or even eliminating the primary stressor. Flavonoids are key compounds for the development of a new generation of therapeutic agents that are clinically effective in treating neurodegenerative diseases. Regular consumption of flavonoids has been associated with a reduced risk of neurodegenerative diseases. In addition to their antioxidant properties, these polyphenolic compounds exhibit neuroprotective properties by their interaction with cellular signaling pathways followed by transcription and translation that mediate cell function under both normal and pathologic conditions. This review focuses on human intervention studies as well as animal studies on the role of various flavonoids in the prevention of neurodegenerative diseases.

Keywords: antioxidant; bioactive compounds; cellular signaling; cognitive functions; flavonoids; mitochondria; neurodegenerative diseases; neuroprotection; oxidative stress.

FIGURE 1

The modulation of neuronal survival and death protein kinase pathways by flavonoids. The activation of PI3K/Akt, ERK1/2, and PKC pathways acts to stimulate neuronal survival through the induction of prosurvival or antiapoptotic genes and via inhibition of proapoptotic proteins. JNK and p38 are stress-activated pathways and cause neuronal death via activation of c-Jun and other AP-1 proteins; they lead to apoptosis and neuronal death. In addition, the inhibitory actions of flavonoids within the JNK and p38 pathways are likely to be neuroprotective in the presence of stress signals. However, flavonoids have neuroprotective and neuromodulatory properties and prevent neuronal function via inhibitory and stimulatory actions at these signaling pathways. AP-1, activated protein 1; ARE, antioxidant response element; ASK1, apoptosis signal-regulating kinase 1; Bad, Bcl-xL/Bcl-2–associated death promoter; Bax, BCL2-associated X protein; bcl-w, BCL2-like 2; bcl-xL, BCL2-like 1; bcl-2, B-cell CLL/lymphoma 2; BDNF, brain-derived neurotrophic factor; CREBP, cAMP response element-binding protein; ERK, extracellular signal-regulated protein kinase; HO-1, heme-oxygenase 1; JNK, c-Jun N-terminal kinase; Mdm2, murine double minute 2; Nrf2, NF-E2–related factor 2; PI3K/Akt, phosphatidylinositol-3 kinase/Akt; PKC, protein kinase C.