Contacts:
Sarah Goodwin

Kathi Ovnic
Holly Korschun
JUNE 24, 1999
EMORY SCIENTISTS IDENTIFY DRUG STRATEGY TO LIMIT BRAIN CELL DAMAGE DURING STROKE

Emory University researchers have identified a new strategy for developing anti-stroke drugs that could protect brain cells from damage during a stroke while at the same time avoiding unacceptable side effects encountered with other anti-stroke drugs. The drugs would represent significant improvements on a class of pharmaceuticals called phenylethanolamines that already have been identified as potentially beneficial in the treatment of stroke.

Raymond J. Dingledine, Ph.D., professor of pharmacology at Emory University School of Medicine, explains that phenylethanolamines are effective because they block communication between neurons in the brain that is mediated by NMDA (N-methyl-D-aspartate) receptors. During ischemic stroke, when the blood supply to a part of the brain is cut off due to a blood clot or constriction of a blood vessel, NMDA receptors are activated and contribute to cell degeneration and death in the stroke area and surrounding tissue.

Although several kinds of phenylethanolamines already have been tested in early clinical trials for stroke, the drugs indiscriminately blocked NMDA receptors scattered throughout the brain. Side effects caused by blocking receptors in healthy tissue included ataxia (muscular incoordination), hallucinations and cardiovascular problems. Also, because the drugs were administered after the onset of a stroke, their neuroprotective effects were limited. The most severe damage to brain cells occurs within the first several hours following a stroke, leaving only a small window of opportunity for effective treatment.

The Emory investigators have identified a mechanism by which NMDA receptors are blocked only in the area surrounding the stroke, thus preventing the side effects encountered when healthy brain tissue is affected.

The new strategy, Dr. Dingledine explains, hinges on the understanding of a key difference in pH balance between stroke-affected brain tissue and healthy brain tissue. The stroke-affected area becomes more acidic than normal brain tissue due to the buildup of anaerobic metobolites, such as lactic acid, when the flow of blood is stopped and the area is deprived of oxygen. The normal brain tissue pH of approximately 7.5 is reduced in ischemic (stroke-damaged) tissue to as low as 6.5.

The investigators hypothesized that an ideal NMDA-blocking drug would be inactive at normal brain pH levels but would be activated at the lower pH values that occur during stroke. Using Xenopus oocytes (large frog eggs), they have refined the mechanism by which phenylethanolamines can selectively target areas of stroke-affected tissue.

"Our strategy allows us to optimize one class of NMDA antagonists because they are potentiated at a low pH," says Dr. Dingledine, "We already have identified a compound that has an 18-fold increase in blocking potency, and we would ideally like to see a 300-fold increase."

Not only would this new approach limit the side effects of NMDA blockers, he explains, it also would allow physicians to administer an anti-stroke drug to at-risk patients chronically, thus ensuring that the drug is "on board" before a stroke occurs in order to minimize cell damage. Dr. Dingledine believes the same class of compounds could also prove useful in limiting brain damage from epilepsy and trauma.

The ongoing research was reported in the December 1998 issue of the journal Nature Neuroscience. The research has been supported by AES/EFA Fellowships, the National Institutes of Health and the John Merck Fund.