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

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.