The mechanisms of action of flavonoids in the brain: Direct versus indirect effects

Highlights

• Flavonoids modulate brain function and behavior in both rodents and humans.

• Long-term supplementation in rodents suggests modulation of brain synaptic plasticity.

• Acute studies in humans improve cerebral blood flow and cognitive function.

• This review addresses both direct and indirect mechanistic actions of flavonoids.

Abstract

The projected increase in the incidence of dementia in the population highlights the urgent need for a more comprehensive understanding of how different aspects of lifestyle, in particular exercise and diet, may affect neural function and consequent cognitive performance throughout the life course. In this regard, flavonoids, found in a variety of fruits, vegetables and derived beverages, have been identified as a group of promising bioactive compounds capable of influencing different aspects of brain function, including cerebrovascular blood flow and synaptic plasticity, both resulting in improvements in learning and memory in mammalian species. However, the precise mechanisms by which flavonoids exert these actions are yet to be fully established, although accumulating data indicate an ability to interact with neuronal receptors and kinase signaling pathways which are key to neuronal activation and communication and synaptic strengthening. Alternatively or concurrently, there is also compelling evidence derived from human clinical studies suggesting that flavonoids can positively affect peripheral and cerebrovascular blood flow, which may be an indirect effective mechanism by which dietary flavonoids can impact on brain health and cognition. The current review examines the beneficial effects of flavonoids on both human and animal brain function and attempts to address and link direct and indirect actions of flavonoids and their derivatives within the central nervous system (CNS).

Introduction

The increase in incidence and prevalence of neurodegenerative diseases, along with the absence of new and effective drug treatments to treat such diseases, highlights the need for a more comprehensive understanding of how different aspects of lifestyle, such as exercise and diet, may influence brain disorders in a preventative manner, affecting long-term neural function and consequent cognitive performance. In particular, flavonoids, found in a variety of fruits, vegetables and beverages, have been recognized as promising plant-based bioactives capable of influencing different aspects of synaptic plasticity, thus resulting in improvements in memory and learning in both animals and humans (Williams and Spencer, 2012, Spencer, 2008, Rodriguez-Mateos et al, 2014a). Indeed, evidence has emerged from human intervention trials that demonstrate consumption of flavonoid-rich foods is associated with cognitive benefits (for a review see Macready et al, 2009, Kennedy, 2014, Nehlig, 2013). The mechanisms by which flavonoids exert these actions on cognitive performance are currently being elaborated, with evidence from long-term supplementation in animal models suggesting that they can modulate synaptic plasticity through activation of neuronal receptors, signaling proteins and gene expression (Rendeiro et al, 2012, Rendeiro et al, 2013a, Spencer, 2007, Williams et al, 2008, van Praag et al, 2007) (Fig. 1). However, the ability of flavonoids to directly modulate brain plasticity may be dependent to some extent on their accessibility to the brain, which is likely to vary based on the structural characteristics of in vivo flavonoid metabolites (Youdim et al., 2004, Youdim et al, 2003). As such, whether flavonoid induced cognitive effects are mediated directly, within the brain or involve other mechanisms triggered from the periphery remains unclear.

With respect to the latter, there is substantial evidence in support of the beneficial effects of flavonoids on the peripheral vascular health (Wang et al., 2014, McCullough et al, 2012, Hooper et al, 2012, Mink et al, 2007). Notably, flavanols (Heiss et al, 2007, Heiss et al., 2010, Schroeter et al, 2006, Schroeter et al, 2010, Ried et al., 2012, Ellinger et al., 2012) and anthocyanins (Rodriguez-Mateos et al, 2014b, Rodriguez-Mateos et al, 2013, Cassidy et al., 2011) have shown capable of promoting clinically significant improvements in endothelial-dependent peripheral vascular function (measured using flow mediated dilatation of the brachial artery) and blood pressure. Such effects seem to be mediated by the actions of absorbed flavonoid metabolites on artery nitric oxide (NO) bioavailability, through their potential to either activate endothelial nitric oxide synthase (eNOS) (Schroeter et al, 2006, Heiss et al, 2005, Moreno-Ulloa et al., 2014) and/or inhibit nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (Rodriguez-Mateos et al, 2013, Takumi et al, 2012) in the endothelium. The extent to which such benefits in vascular responses in peripheral arteries might be translatable to benefits in cerebral arteries and improved vascularization of the brain is currently being explored, with some encouraging clinical data showing increases in cerebral blood flow (CBF) matching closely the timing of peripheral responses following flavanols' intake (Francis et al., 2006, Fisher et al., 2006, Lamport et al, 2015). As such, it has been hypothesized that improvements in human cognitive function observed following flavonoid intake might be partly mediated by increases in CBF (Brickman et al., 2014) (Fig. 1). The ability of flavonoids to facilitate CBF is significant given that data indicate that accentuated declines in brain blood perfusion occur in parallel to aging and other neurological disorders closely implicated to the development of various dementias (Girouard and Iadecola, 2006, Iadecola, 2004, Ruitenberg et al, 2005, Nagahama et al, 2003).

Despite clear evidence regarding the acute vascular effects of flavonoids shown in humans (Schroeter et al, 2006, Schroeter et al, 2010, Rodriguez-Mateos et al, 2013, Heiss et al, 2005) and medium/long-term changes in synaptic plasticity markers demonstrated in animal studies (Rendeiro et al., 2012, Spencer, 2009a, Spencer, 2010), the basic mechanisms of action of flavonoids in the brain remain to be established. In particular, the impact of flavonoids' on peripheral and cerebral blood flow reinforces the importance of understanding to what extent cognitive improvements are mediated by circulating metabolites in the periphery or/and directly by flavonoid metabolites within the brain. In the present review, we summarize human and rodent studies addressing mechanisms of action of flavonoids in brain function, and will specifically highlight how flavonoid modulation of peripheral and cerebral blood flow might affect synaptic plasticity processes and cognitive function.