SEATTLE—Infarct volume after acute stroke can be reduced by ethanol in combination with caffeine or bioflavonoids-at least in experimental rats, according to James Grotta, MD. At the 124th Annual Meeting of the American Neurological Association, he presented his latest findings on the impact of common dietary ingredients on ischemic infarct size in a rodent model.

Along with colleagues at the University of Texas, Dr. Grotta induced moderate ischemic strokes in rats by occluding the common carotid and middle cerebral arteries, and then evaluated the effects of caffeine, ethanol, and bioflavonoids, alone and in various combinations, on the size of the resulting infarct, using water as a placebo control. Infarct size was determined with triphenyltetrazolium chloride (TTC), a staining agent that differentiates vital from dead tissue. Dr. Grotta is Professor of Neurology and Director of the Stroke Program at the University of Texas Medical School, Houston.

NEUROTOXIC OR NEUROPROTECTIVE?

Previous evidence has suggested a neurotoxic potential for both caffeine and alcohol in certain circumstances; however, the latest findings suggest neuroprotection, Dr. Grotta pointed out. A combination of oral 10% ethanol and 10 mg/kg of caffeine showed the greatest efficacy in the experimental stroke model, reducing infarct size to only 12.1% of control. Intravenous 10% ethanol and 10 mg/kg of caffeine given 30, 60, or 90 minutes after middle cerebral artery/common carotid occlusion produced significantly reduced infarct volumes of 25.8%, 39.3%, and 35.6%, respectively, compared to control.

When given three hours after stroke, however, the ethanol/caffeine combination failed to demonstrate any protective effect. As in the case of thrombolytic therapies such as tissue plasminogen activator, early treatment appears critical. Also in the animal model, 50 mg/kg of bioflavonoids with 10% ethanol given orally decreased infarct volume to 56.1% of control.

A COMPLEX INTERACTION

Although alcohol is known to be neurotoxic to the central nervous system in large doses, epidemiologic evidence suggests that moderate alcohol consumption protects against ischemic stroke, Dr. Grotta noted. "Caffeine," he added, "probably affects adenosine receptors and could increase or decrease glutamate release." However, given separately, neither ethanol, caffeine, nor bioflavonoids had any beneficial impact on infarct size. The combination of alcohol and caffeine, Dr. Grotta speculated, may somehow "tweak the neurotransmitter systems optimally," but the exact mechanism of neuroprotection remains a mystery. Acute administration seems to be the key, as no neuroprotective effect was observed in rats chronically exposed to caffeine and alcohol.

"We shouldn't discount nonconventional treatments," said Pierre Fayad, MD, commenting on Dr. Grotta's findings. Dr. Fayad is Associate Professor of Neurology at Yale University, Co-Director of the Yale Cerebrovascular Center, and Director of the Yale Vascular Neurology Program. Further studies, said Dr. Fayad, are surely warranted.

It is difficult to understand how a combination of alcohol and caffeine may affect the injured brain, Dr. Fayad continued, since their individual effects on the brain are also unclear. Acting in combination, alcohol and caffeine may trigger some mechanism that does not operate with either substance alone, he speculated.

He emphasized that "no one should rush to use this combination without further testing." Before clinical trials in humans are considered, he believes that the caffeine/alcohol hypothesis should be tested in other experimental models of stroke and in other animal species.

TOO SOON TO TELL?

Some recent experimental stroke treatments that were beneficial in animal models were useless or even detrimental in humans, Dr. Fayad pointed out. Consequently, patients could actually make things worse by trying this proposed combination prematurely, he cautioned. And because some stroke patients have difficulty swallowing, not all could safely drink an alcohol and caffeine cocktail, he added.

An antioxidant effect of alcohol might be responsible for its observed acute benefits, said Philip Gorelick, MD, MPH, who was also asked to comment on the recent finding. Dr. Gorelick is Professor and Director of the Section of Cerebrovascular Disease in the Department of Neurology at Rush Medical College, Chicago. He also speculated that "caffeine must upregulate certain receptors" and thereby limit ischemic damage. However, Dr. Gorelick acknowledged, these proposed mechanisms do not account for the observation that alcohol and caffeine worked only in combination.

Dr. Grotta would like to see the study results replicated in another laboratory and then pursue formal dose escalation studies. Nonpharmaceutical sources may be approached for funding, he added, due to the nonproprietary nature of the agents in question.

—Andrew Nathan Wilner, MD
Contributing Writer

Return to table of contents