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Review
. 2016 Sep;18(3):487-95.
doi: 10.1007/s12017-016-8418-6. Epub 2016 Jun 24.

Recommendations for Development of Botanical Polyphenols as "Natural Drugs" for Promotion of Resilience Against Stress-Induced Depression and Cognitive Impairment

Libby Ward  1 , Giulio Maria Pasinetti  2   3
Affiliations
Review

Recommendations for Development of Botanical Polyphenols as "Natural Drugs" for Promotion of Resilience Against Stress-Induced Depression and Cognitive Impairment

Libby Ward et al. Neuromolecular Med. 2016 Sep.

Abstract

Extensive evidence has demonstrated that psychological stress has detrimental effects on psychological health, cognitive function, and ultimately well-being. While stressful events are a significant cause of psychopathology, most individuals exposed to adversity maintain normal psychological functioning. The mechanisms underlying such resilience are poorly understood, and there is an urgent need to identify and target these mechanisms to promote resilience under stressful events. Botanicals have been used throughout history to treat various medical conditions; however, the development of botanical compounds into potential preventative and therapeutic agents in studies promoting brain health is hindered by the fact that most orally consumed botanicals are extensively metabolized during absorption and/or by post-absorptive xenobiotic metabolism. Therefore, the primary objective of this review article is to provide recommendations for developing natural compounds as novel therapeutic strategies to promote resilience in susceptible subjects. The development of botanical polyphenols to ultimately attenuate mood disorders and cognitive impairment will rely on understanding (1) the absorption and bioavailability of botanical polyphenols with emphasis on flavan-3-ols, (2) the characterization of tissue-specific accumulation of biologically available polyphenols and their mechanisms of action in the brain, and eventually (3) the characterization of biologically available polyphenol metabolites in mechanisms associated with the promotion of resilience against mood disorders and cognitive impairment in response to stress. We also summarize exciting new lines of investigation about the role of botanicals such as polyphenols in the promotion of cognitive and psychological resilience. This information will provide a strategical framework for the future development of botanicals as therapeutic agents to promote resilience, ultimately preventing and/or therapeutically treating cognitive impairment and psychological dysfunction.

Keywords: Botanicals; Microbiome; Polyphenols; Resilience; Sleep deprivation-induced cognitive impairment; Stress-induced depression.

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Conflict of interest statement

Conflict of Interest

The authors declare that they have no conflict of interest.

Figures

Fig. 1
Fig. 1. Representative structures of polyphenols from grape and grape-derived products
Representatives of flavanols: A) catechin and B) epicatechin gallate. Representatives of flavonols: C) quercetin and D) myricetin. Representative of stilbenes: E) RSV. Representative of phenolic acids: F) dihydrocaffeic acid.
Fig. 2
Fig. 2. Brain-bioavailable polyphenol metabolites promote neuroplasticity mechanisms
Polyphenols modulate processes leading to synapse growth and increased receptor density. (1) Polyphenol metabolites activate the CREB pathway, thus increasing the expression and release of brain-derived neurotrophic factor from the synapse. (2) Elevated brain-derived neurotrophic factor expression binds to pre- and postsynaptic tropomyosin receptor kinase B receptors. (3) This triggers glutamate release, PI3K/mTOR signaling, and Arc IEG synthesis. (4) Sustained activation of mTOR leads to enhanced translational efficiency, while IEGs may influence expression of scaffolding proteins, increase receptor density and ultimately synaptic efficacy. Adapted from (Spencer, 2009).
Fig. 3
Fig. 3. Interpersonal differences in gut microbiota composition affect health benefits of polyphenol-rich botanicals
After oral consumption, monomeric (and to a lesser extent, dimeric) polyphenols are absorbed by the small intestine, with or without enterocyte modification by phase II metabolism (e.g., glucuridation). Most dietary polyphenols, particularly multimeric ones, are not absorbed by the small intestine and are passed to the colon where microbial metabolism converts them into simple phenols, such as phenolic acids. Some of these phenolic acids are absorbed, with or without colonocyte modification by phase II metabolism. Absorbed polyphenol metabolites and phenolic acids may undergo additional phase II metabolism, primarily by the liver, before they are delivered to target tissues, such as blood cells and the brain. The schematic depicts interpersonal microbiota diversity with “red” bacterial strains representing those required to generate select bioactive phenolic acids capable of modulating the cellular/molecular mechanisms underlying psychological and/or cognitive resilience.
Fig. 4
Fig. 4. Resilience to depression and anxiety
Phenolic metabolites from dietary botanical supplements (i) reduce RSDS-induced inflammation and (ii) directly attenuate synaptic plasticity changes, which will lead to resilience to psychological dysfunction.
Fig. 5
Fig. 5. Resilience to sleep deprivation-induced cognitive dysfunction
Phenolic metabolites (a) promote CREB signaling and (b) modulate the expression of IEGs that are necessary for memory consolidation, which will lead to resilience to SD-mediated cognitive dysfunction.
Fig. 6
Fig. 6
Schematic of recommendations for the development of botanical polyphenols into “natural drugs”
See this image and copyright information in PMC

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