I'm sure it's hard to tell if a mouse is having hallucinations. How long will this take to be proven in humans? Whom is updating the stroke strategy for this idea?
http://news.emory.edu//stories/2015/02/traynelis_neuron_nmda_stroke/index.html?
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: the side effects
included disorientation and hallucinations.
Now researchers have found a potential path around this obstacle. The results were published in Neuron.
"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," says senior author Stephen Traynelis,
PhD, professor of pharmacology at Emory University School of Medicine.
"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, PhD collaborated with chemists Dennis
Liotta, PhD and James Snyder, PhD. The co-first authors of the Neuron
paper are pharmacology instructor Hongjie Yuan PhD, chemistry
postdoctoral fellow Gordon Wells, PhD and Scott Myers, PhD, director of
drug discovery at Atlanta-based pharmaceutical company NeurOp.
In medicinal chemistry terms, 93-31 is ten times more potent at pH
6.9, typical for ischemic tissue with an insufficient blood supply, than
at pH 7.6, close to the value for healthy brain tissue.
In collaboration with Katherine Nicholson, PhD at Virginia
Commonwealth University, the researchers tested 93-31 on mice trained to
press a lever when they detect low levels of PCP. When researchers
substituted 93-31 for PCP, the mice did not perceive 93-31’s subjective
effects to be similar enough to PCP’s to respond by pressing levers in
the same way.
Doses of 93-31 that had a positive effect in the stroke model did not
seem to impair coordination or motor function. The mice could still
hold onto a turning rod, in contrast with mice dosed with other NMDA
receptor antagonists.
The research that led to 93-31’s identification has been a platform
for further drug discovery efforts by NeurOp, according to the company’s
CEO, Barney Koszalka, PhD. However, 93-31’s pharmaceutical profile may
not be optimal for further development, he says. In mouse experiments in
the Neuron paper, 93-31 was either injected directly into the brain or into the body cavity.
NeurOp is developing a related candidate drug as a potential
preventive measure for people who experience subarachnoid hemorrhage,
because they have a high risk of a secondary stroke-like event for days
after the initial hemorrhage. NeurOp is completing safety studies and is
planning to file an Investigational New Drug application with the FDA
later in 2015.
"We are taking an analogue of the compound identified in the Neuron
paper forward as a post-surgical treatment for individuals that have
suffered a subarachnoid hemorrhage," Koszalka says. "The pH boost we see
with this series of subunit specific NMDA modulators is expected to
provide an additional safety advantage."
The research was supported by the National Institute of Neurological
Disorders and Stroke (NS036654, NS036604) and by the Advanced Technology
Development Center and EmTech Bio.
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