Polyphenols as adjunctive treatments in psychiatric and neurodegenerative disorders: Efficacy, mechanisms of action, and factors influencing inter-individual response

Highlights

• Polyphenols may be beneficial to psychiatric and neurodegenerative disorders.

• Potential mechanisms of action include modulating gut microbiome and gene expression.

• Differences in metabolism and pro-oxidant properties may affect clinical outcomes.

• Further clinical data are required to establish efficacy and optimal dosing regimens.

Abstract

The pathophysiology of psychiatric and neurodegenerative disorders is complex and multifactorial. Polyphenols possess a range of potentially beneficial mechanisms of action that relate to the implicated pathways in psychiatric and neurodegenerative disorders. The aim of this review is to highlight the emerging clinical trial and preclinical efficacy data regarding the role of polyphenols in mental and brain health, elucidate novel mechanisms of action including the gut microbiome and gene expression, and discuss the factors that may be responsible for the mixed clinical results; namely, the role of interindividual differences in treatment response and the potentially pro-oxidant effects of some polyphenols. Further clarification as part of larger, well conducted randomized controlled trials that incorporate precision medicine methods are required to inform clinical efficacy and optimal dosing regimens.

Introduction

The pathophysiology of psychiatric and neurodegenerative disorders is complex and multifactorial. Shared elements of their pathophysiology include (but are not limited to) impairments in mitochondrial respiration [[1], [2], [3], [4]], mitochondrial dynamics in the brain and periphery [[5], [6], [7], [8], [9]], and dysfunction of the electron transport chain [[1], [2], [3], [4]]. Both psychiatric and neurodegenerative disorders are also associated with chronic oxidative and nitrosative stress [[10], [11], [12], [13], [14], [15]] including compromised anti-oxidant defences with downregulation of the glutathione [[16], [17], [18], [19]] and Nrf-2 related pathways [[20], [21], [22], [23]].

Other common factors underpinning the pathophysiology of these neurodegenerative and psychiatric illnesses include the presence of predominantly activated microglia, with the resultant release of a range of neurotoxins including proinflammatory cytokines, cyclooxygenase-2 (COX-2), prostaglandin 2, and quinolinic acid, leading to the development of neuroinflammation and neurotoxicity [[24], [25], [26], [27]]. Prolonged activation of microglia also begets astrogliosis [24,25], leading to compromised neural-glial interactions, disruption of the neurovascular unit and the development of glutamate-mediated excitotoxicity following an over-activation of NMDA neuroreceptors [28,29]. Other shared abnormalities underpinning the pathophysiology of these disorders include impaired neurogenesis, compromised blood brain barrier integrity, and dysregulation of neurotransmitters such as serotonin and norepinephrine [30] (reviewed in Ref. [31]).

Furthermore, reduced peripheral and brain levels of brain-derived neurotrophic factor (BDNF) is an important component in the pathogenesis of these disorders. BDNF influences plasticity of GABAergic and glutamatergic synapses and modulates serotonergic and dopaminergic neurotransmission. BDNF also engages in paracrine and autocrine signalling on pre and post synaptic terminals and plays an indispensable role in synaptic plasticity and the formation of long-term memory [32]. These functions are largely driven by a complex relationship with N-methyl-d-aspartate (NMDAR) and reduced BDNF levels are a cause of NMDAR hypofunction [32]. In particular, decreased BDNF levels result in a reduction of NMDAR input onto GABA inhibitory interneurons thereby, relieving the normal inhibition of glutamatergic output, which subsequently disrupts the central signal-to-noise ratio resulting in abnormal synaptic behaviour and severe cognitive deficits [[33], [34], [35]].

Each illness is also characterised by widespread epigenetic dysregulation in the brain and periphery [36] and extensive dysregulation of cellular signalling pathways involving nuclear factor-κB (NF-κB), Akt, SIRT-1, Peroxisome proliferator-activated receptors (PPARs) and Glycogen synthase kinase 3 (GSK-3) [[37], [38], [39], [40], [41]]. Finally, there is accumulating evidence to suggest that gut microbiota composition changes, increased intestinal permeability, commensal antigen translocation into the blood stream, and dysfunctional microbiota-gut-brain axis contribute to the pathogenesis and pathophysiology of the aforementioned disorders [[42], [43], [44], [45], [46]].

Numerous animal studies have reported decreased microglial activity and reduced production of proinflammatory cytokines, nitric oxide (NO), inducible nitric oxide synthase (iNOS), quinolinic acid, and COX2 following the administration of polyphenols (reviewed in Ref. [47]). The in vivo evidence extends to improved astrocyte function, reduced levels of glutamate-mediated NMDA receptor excitotoxicity and neuromodulatory properties [[48], [49], [50]]. There is also accumulating evidence of increased activity of PPARs, BDNF and Nrf-2 in the brains of animals following polyphenol ingestion [[51], [52], [53]]. Several research teams have also reported decreased activity of NF-κB and increased activity of SIRT-1 in the central nervous system (CNS) of rodents following prolonged polyphenol ingestion [54,55]. Moreover, numerous studies have reported favourable effects on the composition of the microbiota [56] and gene expression mediated by changes in DNA methylation, histone acetylation and miRNA expression [57].

There is a considerable and accumulating body of epidemiological evidence demonstrating a significant correlation between polyphenol-rich dietary patterns and a reduced risk of developing neurodegenerative disorders such as cognitive impairment and dementia [[58], [59], [60], [61]]. For example, a greater intake of total and polyphenol subclasses was associated with improved language and verbal memory compared to a lower consumption [62]. Furthermore, there is a growing body of epidemiological evidence suggesting that adherence to a high polyphenol diet may improve depression and anxiety [[63], [64], [65], [66], [67]]. For example, a greater consumption of flavonoid subclasses was associated with a reduced risk of depression over 10 years in the Nurses Health Study cohort [62].

Despite the above reported effects of polyphenols, preliminary results from human trials in neuropsychiatric or neurodegenerative diseases have been mixed [68]. Many reasons have been proposed to explain these findings, most notably poor bioavailability, limited ability to cross the blood-brain barrier (BBB), large inter-individual variation in pharmacokinetics, and potentially cytotoxic effects at high doses [69]. There is a considerable body of animal model-based evidence regarding the metabolism, effectiveness, mechanisms of action, interaction with the microbiota, epigenetic regulation and pro-oxidative actions of polyphenols [70].

We aim to review the evidence in each of these areas with reference to four distinct members of the polyphenol family: namely curcumin, resveratrol, quercetin, and anthocyanins. The aim of this review is to highlight the emerging clinical trial and preclinical efficacy data regarding the role of polyphenols in mental and brain health, elucidate novel mechanisms of action including the gut microbiome and gene expression, and discuss the factors that may be responsible for the mixed clinical results; namely, the role of interindividual differences in treatment response and the potentially pro-oxidant effects of some polyphenols [71].