A new study has revealed that a NMDA receptor antagonist called 93-31 can reduce the volume of damaged brain tissue by more than half in a mouse model of ischemic stroke. Researchers also found that administering 93-31 to the mice does not seem to lead to the psychoactive side effects seen with other NMDA receptor antagonists.
In the 1990s, researchers identified a class of drugs, NMDA receptor antagonists, that showed promise in the area of stroke. NMDA receptors are abundant on the surfaces of brain cells and play key roles in healthy processes such as memory formation. The drugs phencyclidine (also known as PCP) and ketamine are NMDA receptor antagonists. Animal studies revealed that NMDA receptor antagonists could limit damage to the brain due to stroke. Their ability to block all subtypes of NMDA receptors is thought to account for their psychoactive side effects. However, side effects like disorientation and hallucinations complicated testing the drugs in a clinical setting.
Senior author Stephen Traynelis at Emory University School of Medicine said, "We have found neuroprotective compounds that can limit damage to the brain during ischemia associated with stroke and other brain injuries, but have minimal side effects. These compounds are most active when the pH is lowered by biochemical processes associated with injury of the surrounding tissue. This is a proof of concept study that shows this mechanism of action could potentially be exploited clinically in several conditions, such as stroke, traumatic brain injury (TBI) and subarachnoid hemorrhage."
In brain tissue affected by stroke or TBI, the environment becomes more acidic because of the lack of oxygen and the buildup of metabolites such as lactic acid. Additionally, NMDA receptors get overstimulated by an increase in the neurotransmitter glutamate, enough to kill cells. Researchers reasoned that the NMDA receptor antagonists whose activity is dependent on acidic conditions should, at the right dose, be active only in the injured areas of the brain.
The results have been published in Neuron.