Researchers Zero in on Neuroprotective Pathway of Flavanols in Stroke
By Pauline Anderson
Medscape Medical News
May 12, 2010 — Researchers believe they have nailed down the main pathway by which epicatechin (EC), a flavanol found in dark chocolate and other foods, protects against damage from a stroke.
In mouse models, they showed that EC provides neuroprotection against brain injury induced by transient middle cerebral artery occlusion and N-methyl-D-aspartate (NMDA)–induced excitotoxicity and that this protection occurs through activation of a pathway involving the heme oxygenase 1 (HO1) enzyme and the transcriptional factor Nrf2.
"One of the goals of this study was to understand how EC is protective," said study author Sylvain Dore, PhD, associate professor in the Department of Anesthesiology and Critical Care Medicine and Department of Pharmacology and Molecular Sciences at Johns Hopkins University, Baltimore, Maryland. "We have identified what we believe is part of that pathway; we're not saying it's the only pathway, but we think it's the major one."
The study results suggest that the EC compound does not have a direct antioxidant effect, as previously believed, but rather is activated through an indirect antioxidant pathway, he said.
The findings could lay important groundwork for designing future clinical trials using this flavanol. "If you don't know how an agent works, then it's very difficult to estimate the dose, it's very difficult to estimate potential risks, and it's difficult to appreciate the complexity of the system," said Dr. Dore.
The study was published online May 5 in the Journal of Cerebral Blood Flow and Metabolism.
Reduced Infarct Volume
In this work, the researchers administered EC (5, 15, and 30 mg/kg) or distilled water to 20 laboratory mice 90 minutes before inducing an ischemic stroke. The infarct volume of the mice receiving EC was significantly smaller than that of the control mice and the effect was dose dependent.
Table. Infarct Volume With Epicatechin Treatment vs Control
Group
Infarct Volume, %
P
Control
40
?
5 mg/kg
31.3
<.05
15 mg/kg
30.9
<.04
30 mg/kg
27.6
<.002
The 30-mg/kg dose of EC also offered neurologic protection when administered after an induced stroke. The 10 mice that were treated with this dose of EC 3.5 hours after an insult had significantly smaller infarct volumes at 72 hours — 33.5% compared with 46.6% for the 10 control mice receiving distilled water (P < .04).
However, the agent did not appear to work at 6 hours. "That was somewhat expected because interventions after a stroke have to done very quickly," said Dr. Dore.
EC appeared to also work on another model of brain injury — NMDA-induced excitotoxicity.
The researchers determined that the neuroprotective effect of EC is dependent on the presence of HO1. The results "suggest that EC regulates Nrf2, thereby enhancing the protective defense mechanisms through the HO1 neuroprotective pathway," the study authors write.
According to Dr. Dore, EC by itself may not directly shield brain cells from free radical damage, but along with its metabolites, it may be prompting the cells to defend themselves.
This study adds to the mounting evidence that flavanols and other polyphenols have a protective effect in cerebral ischemia. Flavanols have been shown to improve vasorelaxation. The simple chemical structure of flavanols may interact with specific cellular and molecular targets, thereby mediating a wide range of biologic activities, according to the study authors.
In addition to dark chocolate, flavanols and other polyphenols are found in red wine, tea, grapes, and other fruits and vegetables.
Dr. Dore is cautious about overstating the health benefits of dark chocolate. "We have to be very careful because chocolate by itself is not healthy; it's full of saturated fat and sugar and doesn't have many other nutrients."
Health-Enhancing Cocoa
Cocoa, on the other hand, is rich in flavanols but is not sweet or full of fat. Research on natives from Kuna Island near Panama, who consume large amounts of a drink made from cocoa extract rich in EC, have a relatively low incidence of cardiovascular disease. Because their CVD levels increase when they adopt a western lifestyle, the protection is not deemed to be genetic but due to their diet.
Dr. Dore pointed out that although significantly increasing consumption of flavanols like EC might seem like a good strategy to improve health, potential side effects remain unknown. "In this study, we show the protective effect globally, but the treatment might affect platelets," said Dr. Dore.
The EC flavanol is also quite unstable, he adds. "So even if you drink a lot of cocoa, it doesn't mean that the active compound is still there."
Dr. Dore is keen to learn more about EC's protective mechanism. "It's interesting to show that, yes it's protective, but we'd like to investigate whether it helps more in the vascular aspect or more in the cellular aspect."
Other Neurologic Disorders
The next step for Dr. Dore and his colleagues is to test different models to see whether EC can protect against other neurologic disorders, including chronic conditions like Alzheimer's disease, Parkinson's disease, and indeed "potentially any disease characterized by loss of neurons that would benefit from saving those neurons from dying."
They also want to take a closer look at cocoa to see if it contains beneficial compounds other than flavanol.
Approached for a comment, Robert H. Eckel, MD, professor of medicine at the University of Colorado School of Medicine, Denver, and past president of the American Heart Association, said he found this report of how EC in a rodent model of ischemic stroke might reduce the amount of brain damage to be "interesting."
"However," he pointed out in an email to Medscape Neurology, "the value of this model to stroke in humans and the dosages of the flavanol required remain uncertain."
The study authors have disclosed no relevant financial relationships.
J Cereb Blood Flow Metab. Published online May 5, 2010.