November 15, 1999
Volume 52, No. 12
Dingledine leads advances in brain, stroke research
Emory 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 Dingledine, professor of pharmacology in the medical school, explained 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 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, Dingledine said, 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 frog eggs, they have refined the mechanism by which phenylethan-olamines 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," said 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 explained, 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.
Dingledine believes the same class of compounds could also prove useful in limiting brain damage from epilepsy and injury trauma. The research has been supported by AES/EFA Fellowships, the National Institutes of Health and the John Merck Fund.
Dingledine has also been in the news for discovering that memory and learning are dependent upon the collaboration of specific brain proteins that are separated by a small gap between communicating neurons.
In research reported recently in Science, he and his colleagues studied "synaptic plasticity" of neurons in the hippocampus--the region of the brain involved in memory storage. Because synaptic connections within the nervous system are "plastic," they can change their strength, or increase or decrease in number depending on circumstances. Experience can mold the nervous system by stimulating or repressing electrical activity and can exert a lasting influence on subsequent patterns of behavior, leading to long-term memory.
"The cellular mechanisms underlying activity-induced changes in the strength of communication between neurons ('synaptic plasticity') have been the subject of intense study for the past 25 years," said Dingledine, "and a heated controversy has developed over whether the key changes occur on the presynaptic or postsynaptic membrane. Our data indicate that for one common type of plasticity, essential events leading to plasticity must occur on both sides of the synapse."
Identification of the proteins responsible for synaptic plasticity provides new leads for developing drugs that improve memory and, perhaps, drugs that can relieve forms of chronic pain that also depend on changes in the strength of brain pathways.
This research was supported by the National Institutes of Health, the American Epilepsy Society and Sigma Xi.