Dietary polyphenols as modulators of brain functions: biological actions and molecular mechanisms underpinning their beneficial effects

Abstract

Accumulating evidence suggests that diet and lifestyle can play an important role in delaying the onset or halting the progression of age-related health disorders and to improve cognitive function. In particular, polyphenols have been reported to exert their neuroprotective actions through the potential to protect neurons against injury induced by neurotoxins, an ability to suppress neuroinflammation, and the potential to promote memory, learning, and cognitive function. Despite significant advances in our understanding of the biology of polyphenols, they are still mistakenly regarded as simply acting as antioxidants. However, recent evidence suggests that their beneficial effects involve decreases in oxidative/inflammatory stress signaling, increases in protective signaling and neurohormetic effects leading to the expression of genes that encode antioxidant enzymes, phase-2 enzymes, neurotrophic factors, and cytoprotective proteins. Specific examples of such pathways include the sirtuin-FoxO pathway, the NF-κB pathway, and the Nrf-2/ARE pathway. Together, these processes act to maintain brain homeostasis and play important roles in neuronal stress adaptation and thus polyphenols have the potential to prevent the progression of neurodegenerative pathologies.

Figure 1

Structures of polyphenols. Polyphenols are a group of naturally occurring phytochemicals which are present in high amounts in fruits, vegetables, and natural products and are characterised by the presence of multiple hydroxyl groups on aromatic rings. These compounds are divided into two main categories, the flavonoids and non flavonoids, based on the number of phenol rings and the way in which these rings interact. For the flavonoid group, the major differences between the individual groups arise from the hydroxylation pattern of the ring-structure, the degree of saturation of the C-ring, and the substitution of the 3-position. HBAs, hydroxybennzoic acids; HCAs, hydroxycinammic acids.

Figure 2

Modulation of neuronal dysfunction by dietary polyphenols. In ageing and neurodegenerative diseases, neuronal death can be triggered by specific genetic mutations, neurotoxins, and/or neuroinflammation. Initiating factors promote cellular alterations, including increases in oxidative stress, protein aggregation, DNA damage, and activation of apoptotic cascades. Dietary polyphenols have been observed to protect the brain against such cellular alteration through the modulation of neuronal function against endogenous neurotoxins and inhibition of glial-induced neuroinflammation. Aβ, amyloid beta; CysDA, 5-S-cysteinyldopamine; DHBT1, dihydrobenzothiazine 1; TNF-α, tumor necrosis factor alpha; IL-1β, interleukine-1 beta; CRP, C reactive protein; NO, nitric oxide.

Figure 3

Mechanisms underlying the biological effects of polyphenols. Polyphenols and their in vivo metabolites activate cellular stress-response pathways resulting in the upregulation of neuroprotective genes. For example, both PKC and ERK can activate the nuclear factor erythroid 2-related factor 2 (Nrf2). Nrf2 then translocates to the nucleus and binds to the antioxidant response element (ARE) in genes that encode cytoprotective proteins such as antioxidant enzymes (AOE) and phase 2 (Ph2) enzymes. The transcription factor cAMP-response-element-binding protein (CREB) is also activated by ERK, which induces the expression of brain-derived neurotrophic factor (BDNF), a mediator of neurohormesis. In addition, polyphenols can also regulate the transcription factor NF-κB, which can mediate adaptive cellular stress responses by reducing the expression of inflammatory cytokines. Activated SIRT1 may also inhibit NF-κB and so can reduce the cellular stress response. Another important pathway activated by metabolic and oxidative stress involves transcription factors of the forkhead (FoxO) family, which modulate genes that encode antioxidant enzymes and other stress-response proteins.