Stimulatory Effects of the Flavanols (−)‐Epicatechin and its Enantiomer (+)‐Epicatechin on Frontal Cortex Markers of Neurogenesis
Authors: Villarreal Francisco , Mendoza‐Lorenzo Patricia , Neri‐Gomez Teresa , Manjarrez‐Gutierrez Gabriel , Navarrete‐Yanez Viridiana , Schreiner George , Dugar Sundeep , Ceballos Guillermo , Ramirez‐Sanchez Israel 
Published: June 2021

The consumption of cocoa products rich in flavanols is associated with improvements in measures of cognition. The most abundant flavanol present in cacao is (−)‐epicatechin (Epi) which upon consumption we have demonstrated to beneficially impact measures of neuroinflammation, neurodegeneration, oxidative stress and mitochondrial biogenesis in mouse frontal cortex. The objective of this study was to analyze the effect of either (−)‐Epi or its rare stereochemical analog (+)‐epicatechin on adult mouse brain frontal cortex markers/modulators of neurogenesis. For this purpose, 3 month old male mice (n=5/group) were provided either with water (vehicle; Veh), (−)‐Epi, or (+)‐Epi at 1 mg/kg body weight for 15 days by oral gavage. After the treatment period, brain frontal cortex was isolated for nitric oxide (NO) measurements, Western blotting for nerve growth factor (NGF), eNOS and nNOS and immunohistochemistry for neuronal specific nuclear protein (NeuN), endothelial (CD31) and neurofilament (NF200) markers. Statistical analysis was performed by ANOVA. Results evidence the stimulatory capacity of (−)‐Epi and (+)‐Epi on markers of neuronal proliferation as per the significant increases in NeuN immunoreactive cells (~150% and 240% respectively) as well as an increase in NGF protein levels of ~45% and ~65% when compared to Veh. The assessment of capillary density effects as per the immunostaining of CD31 also yielded significant increases vs. Veh that were greater in magnitude with (+)‐Epi (~400%) vs. (−)‐Epi (~270%). These effects correlated with positive actions of (−)‐Epi and (+)‐Epi on NO levels (figure A, ~150 and 400% respectively) and eNOS (~25 and 50%) and nNOS (~10 and 20%) phosphorylation levels. We also observed significant increases in neuronal cytoskeleton filaments (NF200) with immunostaining which suggest the development of mature axonal extensions which were greater in magnitude in (−)‐Epi (~200%) vs. (+)‐Epi (~170%) vs. Veh. In conclusion, results suggest that flavanols which are present in cacao exert a strong positive effect on recognized markers of neurogenesis and that such effects may be linked to the stimulatory actions on NO. It also appears that (+)‐Epi is more effective in triggering this action. Further studies await to demonstrate the impact that the sustained consumption of the (−) and (+)‐Epi flavanols exerts in measures of cognition in humans and if they may prevent the early development of mild cognitive impairment as seen in the very early phases of dementia.Support or Funding InformationFunded by NIH AG47326 and DK98717 to FV and grant 20151092 to IRS. We are thankful to Cardero Therapeutics, Inc. for providing (+)‐Epi.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.