Neuroprotectant promising in nonhuman primate stroke model
MedWire News: A neuroprotectant that has been successful in rodent stroke models reduces infarct size and improves outcomes in a nonhuman primate stroke model, researchers report in Nature.
Despite much promising research into neuroprotectants in rodent models of stroke, no drug has yet proved effective in humans.
"The current prevailing belief, that neuroprotection in humans is not achievable, arose in response to these failures," say Michael Tymianski (Toronto Western Hospital Research Institute, Ontario, Canada) and colleagues.
To "bridge this biological gap," the researchers used a model of middle cerebral artery (MCA) occlusion in cynomolgus macaques. They treated the macaques with an experimental drug termed Tat-NR2B9c, which disrupts the interactions between postsynaptic density protein (PSD)-95 and neurotoxic signaling pathways. The drug has already proved successful in rodent stroke models.
The macaques received Tat-NR2B9c or placebo 1 hour after 90 minutes of experimental stroke. In a severe stroke model, which cuts off collateral blood flow, four of 10 macaques given placebo died within 48 hours because of brain swelling and uncal herniation. Three of 10 macaques given Tat-NR2B9c died because of surgical or anesthetic complications.
All surviving animals underwent magnetic resonance imaging 24 hours after stroke. At this point, compared with macaques given placebo, those given Tat-NR2B9c had a 44.0% reduction in infarct size on diffusion-weighted imaging (DWI) and a 37.4% reduction on T2-weighted imaging. This benefit persisted at 30 days.
The researchers normalized final infarct sizes to the defect seen on imaging 15 minutes after stroke onset, to allow for the same occlusion producing different infarct sizes in individual animals. This showed that Tat-NR2B9c treatment had produced an average 55% reduction in infarct size on DWI and a 70% reduction on T2-weighted imaging.
Macaques treated with Tat-NR2B9c also had improved scores on a nonhuman primate equivalent of the National Institutes of Health Stroke Scale throughout the 30-day follow up, and performed better in various physical and behavioral tests.
The researchers also tested the effects of Tat-NR2B9c given 1 hour into a 4.5-hour experimental stroke, mimicking a scenario in which neuroprotection is given early and tissue plasminogen activator (tPA) is only administered at the very end of its therapeutic window. Again macaques given Tat-NR2B9c (n=6) had significantly smaller infarct volumes than those given placebo (n=6) and better neurologic and behavioral outcomes.
This "suggests a potential for use of early neuroprotection to extend the benefits of reperfusion therapy even beyond the 4.5-hour window," say Tymianski et al.
They also show that macaques had significantly reduced infarct sizes when given Tat-NR2B9c rather than placebo 3 hours into a 3.5-hour stroke, showing that it could potentially improve outcomes if given only slightly ahead of tPA.
"Our findings using PSD-95 inhibitors may not be generalizable to other neuroprotective strategies," say the researchers. "However, they defeat the current pessimistic belief by demonstrating that pharmacological neuroprotection of the high-order brain of gyrencephalic primates is unequivocally possible.
"Unless there exist fundamental, as yet unknown, relevant differences between such primates and humans, neuroprotection in humans using PSD-95 inhibitors should also be feasible."
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By Eleanor McDermid