Neurotrophic function of phytochemicals for neuroprotection in aging and neurodegenerative disorders: modulation of intracellular signaling and gene expression.

Bioactive compounds in food and beverages have been reported to promote health and prevent age-associated decline in cognitive, motor and sensory activities, and emotional function. Phytochemicals, a ubiquitous class of plant secondary metabolites, protect neuronal cells by interaction with cellular activities, in addition to the antioxidant and anti-inflammatory function. In aging and age-associated neurodegenerative disorders, phytochemicals protect neuronal cells by neurotrophic factor-mimic activity, in addition to suppression of apoptosis signaling in mitochondria. This review presents the cellular mechanisms underlying anti-apoptotic function and neurotrophic function of phytochemicals in the brain. Phytochemicals bind to receptors of neurotrophic factors, and also receptors for γ-aminobutyric acid, acetylcholine, serotonin, and glutamate and estrogen, and activate downstream signal pathways. Phytochemicals also directly intervene intracellular signaling molecules to modify the brain function. Finally, phytochemicals enhance the endogenous biosynthesis of genes coding anti-apoptotic Bcl-2 and neurotrophic factors, such as brain-derived and glial cell line-derived neurotrophic factor. The gene induction may play a major role in the neuroprotective function of dietary compounds shown by epidemiological studies. Quantitative measurement of neurotrophic factors induced by phytochemicals in the serum, cerebrospinal fluid, and other clinical samples is proposed as a surrogate assay method to evaluate the neuroprotective potency. Development of novel neuroprotective compounds is expected among compounds chemically synthesized from the brain-permeable basic structure of phytochemicals.