Revivifying drugs with anti-stroke potential by minimizing side effects

A team of researchers is revivifying drugs with anti-stroke potential by minimizing their side effects.

In the 1990s, neuroscientists identified a class of drugs that showed promise in the area of stroke. NMDA receptor antagonists could limit damage to the brain in animal models of stroke, but one problem complicated testing the drugs in a clinical setting, that is, the side effects included disorientation and hallucinations.

Senior author Stephen Traynelis at Emory University School of Medicine said that they 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.

Traynelis added that 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 and subarachnoid hemorrhage.

In a mouse model of ischemic stroke, a NMDA receptor antagonist called 93-31 can reduce the volume of damaged brain tissue by more than half, researchers found. At the same time, giving mice 93-31 does not seem to lead to the side effects seen with other NMDA receptor antagonists.

The drugs phencyclidine (also known as PCP) and ketamine are NMDA receptor antagonists; their ability to block all subtypes of NMDA receptors is thought to account for their psychoactive side effects. NMDA receptors are abundant on the surfaces of brain cells and play key roles in healthy processes such as memory formation.

In brain tissue affected by stroke or traumatic injury, the environment becomes more acidic because of the lack of oxygen and the buildup of metabolites such as lactic acid. In addition, NMDA receptors get overstimulated by an increase in the neurotransmitter glutamate, enough to kill cells. Researchers reasoned that 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.

To identify the new pH-dependent drugs, Emory pharmacologists led by Traynelis and Ray Dingledine collaborated with chemists Dennis Liotta and James Snyder.

The results are published in Neuron.