Polyphenols and neuroprotection: Therapeutic implications for cognitive decline

Abstract

Dietary polyphenols have been the focus of major interest for their potential benefits on human health. Several preclinical studies have been conducted to provide a rationale for their potential use as therapeutic agents in preventing or ameliorating cognitive decline. However, results from human studies are scarce and poorly documented. The aim of this review was to discuss the potential mechanisms involved in age-related cognitive decline or early stage cognitive impairment and current evidence from clinical human studies conducted on polyphenols and the aforementioned outcomes. The evidence published so far is encouraging but contrasting findings are to be taken into account. Most studies on anthocyanins showed a consistent positive effect on various cognitive aspects related to aging or early stages of cognitive impairment. Studies on cocoa flavanols, resveratrol, and isoflavones provided substantial contrasting results and further research is needed to clarify the therapeutic potential of these compounds. Results from other studies on quercetin, green tea flavanols, hydroxycinnamic acids (such as chlorogenic acid), curcumin, and olive oil tyrosol and derivatives are rather promising but still too few to provide any real conclusions. Future translational studies are needed to address issues related to dosage, optimal formulations to improve bioavailability, as well as better control for the overall diet, and correct target population.

Introduction

The global rise in life expectancy is leading to an increase in age-related non-communicable diseases, with growing trends in cognitive decline and neurodegenerative disorders (GBD, 2018). While a decline in cognitive abilities is para-physiologic at older age (Harman & Martín, 2020), it is important to distinguish such conditions from non age-related cognitive impairment due to pathological states [i.e., dementia or Alzheimer's disease (AD)]. Aging is associated with an impairment of immune system and the establishment of a chronic subclinical inflammation (so-called “inflammaging”) (Franceschi, Garagnani, Parini, Giuliani, & Santoro, 2018), which can be exacerbated at younger ages by obesity and lifestyle factors, including poor physical activity, smoking, and dietary habits (Phillips, 2017). Chronic systemic inflammation is characterized by raise in proinflammatory cytokines [i.e., C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), combined with a reduction of transforming growth factor-beta 1 (TGF-β1) among the most studied] and endothelial dysfunction, which in turn may result in increased blood-brain barrier (BBB) permeability with consequent activation of microglia and development of neuroinflammation (Bettio, Rajendran, & Gil-Mohapel, 2017). These processes may finally result in impairment of neuronal, cerebrovascular, and cognitive function, followed by impairment of executive functions, working memory, and processing speed (Kirova, Bays, & Lagalwar, 2015). The sooner the damage occurs, the more serious the consequences can be, with future development of neurodegenerative diseases, such as dementia and AD (Kelley & Petersen, 2007). The pharmacological indications for dementia and AD are rather poor, with anticholinesterases to be used at earlier stages and the N-methyl-D-aspartate (NMDA) receptor antagonist as elective treatment strategies (Hugo & Ganguli, 2014). Given the limited pharmacological options to treat these conditions, drug discovery in this field has been now focused on the early stages to counteract or, at least, slow down the progression of these neurodegenerative diseases.

Some pathophysiological conditions, such as neuroinflammation, mitochondrial dysfunction, impaired neurogenesis and synaptic plasticity, and reduced cerebral blood flow are consistently involved in cognitive impairment. Thus, it may be hypothesized that dietary factors may target these pathological processes and prevent or control the manifestation of neurodegenerative disorders, including cognitive decline (McGrattan et al., 2019). Among the most attractive molecules of interest for drug discovery and application in the pharmacological setting, dietary polyphenols have recently been the focus of major attention (Bacci, Runfola, Sestito, & Rapposelli, 2021). Polyphenol compounds include a heterogeneous group of molecules with a basic structure characterized by one or more hydroxyl groups binding to one or more aromatic rings linked with one or more sugar residues and/or other compounds, such as amines, carboxylic and organic acids, lipids, and other phenols (Del Rio et al., 2013). Based on their chemical composition, polyphenols are grouped into various families and subfamilies, such as flavonoids (including flavonols, flavan-3-ols, anthocyanidins, flavones, flavanones, isoflavones, and chalcones) and “non-flavonoids” comprising phenolic acids, stilbenes, tyrosol, curcuminoids, lignans, saponin, and tannins (Del Rio et al., 2013). These compounds naturally occur in plant-derived foods and beverages: among the major dietary sources of polyphenols, fruits (i.e., berries, grapes, apples), vegetables (i.e., onions), cocoa products, coffee and tea, olive oil, and curcumin are the most studied (Del Rio, Costa, Lean, & Crozier, 2010). In the plant world, polyphenols exert a number of protective functions, including defense against UV radiation and microbial infections (Pandey & Rizvi, 2009). In humans, dietary polyphenols have been initially investigated for their potent antioxidant activity, but later studies have demonstrated far more articulated actions in the human body, including a clinically-relevant impact on immune system, endothelium, and, only recently, also gut microbiota regulation (Grosso, 2018; van der Merwe, 2021). Taking into account the transformation at colonic level and absorption, the good bioavailability deriving from the ability of some polyphenols to pass, to a various extent, the BBB raised the interest in these molecules as novel neuroprotective tools against neurodegenerative disorders.

While there are numerous mechanistic studies conducted in the laboratory setting suggesting a potential role of polyphenols in advanced cognitive disorders and AD, clinical data in humans are are rather scarce and disappointing (Ansary & Cianciosi, 2020; Colizzi, 2019). In fact, a large body of scientific literature probably overestimates the effects of polyphenols on cognitive outcomes (especially in relation to AD) when comparing mechanistic studies versus clinical evidence from human trials. Misalignment of findings between animal and human studies may depend on the complexity of the condition investigated, not necessarily fully reproduced in the animal models of disease (Fisher & Bannerman, 2019). However, the lack of significant findings may also depend on the specific degenerative pathogenic processes characterizing the AD (amyloid plaques and neurofibrillary tangles) that may lead to a clinical condition not treatable with a dietary intervention (Arshavsky, 2014). Moreover, dietary supplementation with polyphenols may suffer from low dietary intake or poor bioavailability leading to clinically irrelevant effects in the context of an ongoing therapy (Thenmozhi, Manivasagam, & Essa, 2016). Although lack of significant results from human trials conducted on advanced AD patients smoothed the enthusiasm toward polyphenols as a potential agents against cognitive disorders, there is emerging evidence that dietary factors may play a larger role in preventing or mitigating the effects of aging on cognitive status in older adults, opening to the possibility for early intervention through supplementation and diet modification to slow down and counteract cognitive decline (Godos et al., 2020).

The aim of this narrative review is to summarize the most relevant evidence of the effects of polyphenol compounds on cognitive outcomes in healthy older individuals or early stage/mild cognitive impairment (MCI). The potential mechanisms of action underlying the neuroprotective activity of polyphenols, provided from animal or in vitro studies, are discussed to better understand the therapeutic potential of these compounds.