作者：Pauline Anderson
出處：WebMD醫學新聞
May 12, 2010 — 研究者相信，他們確定了epicatechin (EC)這個存在於黑巧克力和其他食物的黃烷醇(Flavanols)對抗中風的主要路徑。
在老鼠模式中，他們顯示EC對於暫時性中腦動脈阻塞引起的腦損傷、以及N-甲基-D-天門冬氨酸(NMDA)引起的興奮性中毒有神經保護作用，這個保護作用透過活化第一型血色素氧化酵素(HO1)以及轉錄因子Nrf2等路徑而達成。
研究作者、約翰霍普金斯大學藥理與分子科學系、麻醉與重症照護醫學系副教授Sylvain Dore博士表示，研究目標之一是瞭解EC如何產生保護，我們已經確認我們找到其中的一個路徑；我們不是說那是唯一路徑，但是相信它是主要路徑。
研究結果認為，EC成分如同之前所認知的，並無直接抗氧化效果，但是，透過間接的抗氧化路徑而活化。
這些研究發現為未來使用黃烷醇的臨床試驗打下重要基礎，Dore博士表示，如果你不知道一個製劑如何作用，那就會難以估計劑量以及可能的風險，也難以理解該系統的複雜度。
這項研究線上發表於5月5日的腦部血流及代謝期刊(Journal of Cerebral Blood Flow and Metabolism)。
【減少梗塞容量】
研究者給予20隻實驗老鼠服用EC (劑量分別為5、15和30 mg/kg)或蒸餾水，90分鐘之後誘發缺血性中風。接受EC的老鼠其梗塞量顯著小於對照組老鼠，且這項效果與劑量有關。
表.使用Epicatechin治療與對照組的梗塞量
| 組別 | <B梗塞量,% | P |
| 控制組 | 40 | |
| 5 mg/kg | 31.3 | <.05 |
| 15 mg/kg | 30.9 | <.04 |
| 30 mg/kg | 27.6 | <.002 |
EC劑量30-mg/kg這組，在誘發中風之後給藥時仍有神經保護效果，中風之後3.5小時，使用此EC劑量治療的10隻老鼠，在72小時時仍有顯著較小的梗塞量：33.5%，使用蒸餾水的10隻對照組老鼠其梗塞量則是46.6%(P < .04)。
不過，在6小時時給藥則未見有效，Dore博士表示，這在意料之中，因為中風後的介入需相當迅速。
EC對於另一類型腦損傷─NMDA引起的興奮性中毒，似乎也有作用。
研究者確認EC的神經保護效果是因為有HO1，作者們寫道，結果認為，EC會調節Nrf2，因此透過HO1神經保護路徑促進保護防禦機轉。
根據Dore博士指出，EC本身並未直接保護腦細胞免於自由基的傷害，而是藉由它的代謝物促進細胞自我防衛。
根據研究作者表示，本研究添加了黃烷醇和其他多酚對腦缺血的保護效果，黃烷醇已經證明可以改善血管鬆弛，黃烷醇的簡單化學構造可和特定細胞與分子標靶產生交互作用，因此調節廣泛的生物活性。
除了黑巧克力之外，黃烷醇和其他多酚可見於紅酒、茶、葡萄與其他蔬果。
Dore博士提醒，不要誇示黑巧克力的健康助益，我們需相當謹慎，因為巧克力本身並不健康；它富含飽和脂肪與糖，別無其他營養成分。
【促進健康的可可亞】
另一方面，可可亞富含黃烷醇，但是不甜也無脂肪。針對巴拿馬附近Kuna島的住民進行研究，這些住民攝食大量由可可亞製成、富含EC的飲品，他們的心血管疾病發生率相對較低，如果他們改採西式生活型態，他們的心血管疾病發生率增加，推論前述的保護力不是因為基因，而是與他們的飲食有關。
Dore博士指出，雖然顯著增加EC等黃烷醇的量可能是改善健康的一個好策略，但是對於可能的副作用仍然未知。在該研究中，我們顯示出全面性的保護效果，但是，此治療影響的可能是血小板。
他指出，EC黃烷醇相當不穩定，所以，即便你喝很多可可亞，不代表有那些活性成分。
Dore博士熱衷於瞭解更多關於EC的保護機轉，顯示它有保護力是有趣的，但是我們將探討它對於血管還是細胞的幫助較多。
【其他神經異常】
Dore博士等人的下一步驟是檢測不同的模式，以探討EC是否可以對抗其他神經異常，包括阿茲海默氏症、巴金森氏症等慢性狀況，甚至任何神經元損失的疾病，都可以藉由這類挽救神經元的治療而獲益。
他們也希望更深入探討可可亞，看它是否含有黃烷醇之外的有益成份。
科羅拉多大學醫學院內科教授、美國心臟協會前任理事長Robert H. Eckel醫師受邀發表評論時表示，他認為，這篇有關EC如何在老鼠缺血性中風模式中減少腦損傷的研究相當有趣 。
不過，他在給Medscape Neurology的電子郵件中寫道，這個模式的價值在於人類的應用，而所需的黃烷醇劑量目前仍未知。
研究作者皆宣告沒有相關財務關係。
J Cereb Blood Flow Metab.線上發表於2010年5月5日。
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.
