Despite much promising animal research on protecting the brain after stroke, no treatments have yet proven to be effective in humans. This disconnect has contributed to both a lack of confidence in the relevance of animal models for certain types of medical research and a growing concern that stroke-related brain damage may not be avoidable in higher-order mammals such as humans. To bridge this gap, a team of researchers led by Michael Tymianski (Toronto Western Hospital Research Institute, Ontario, Canada) has developed a primate model of stroke by occluding the middle cerebral artery in cynomolgus macaques (Macaca fascicularis). Because primates share behavioral, genetic and anatomical characteristics with humans, success in treating stroke in primates should be a more reliable predictor of success in humans.

Tymianski's group used the macaque model to test the efficacy of an experimental stroke treatment that has shown promise in rat studies and found that the treatment reduced infarct size and improved outcomes in the macaques (Nature 483, 213–217; 2012). The scientists state that these findings “defeat the current pessimistic belief by demonstrating that pharmacological neuroprotection of the high-order brain of gyrencephalic primates is unequivocally possible.” Furthermore, they suggest that “[u]nless there exist fundamental, as yet unknown, relevant differences between such primates and humans, neuroprotection in humans... should also be feasible.”

The treatment tested by Tymianski's team inhibits interactions between post-synaptic density protein 95 (PSD-95) and neurotoxic signaling pathways, protecting the brain against stroke-related damage. In the macaque study, experimental stroke was induced for 90 minutes, and either PSD-95 inhibitor or a placebo was administered 60 minutes later. The size of the infarct, or ischemic tissue resulting from the stroke, was assessed by magnetic resonance imaging.

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Infarcts in macaques that received PSD-95 inhibitor were ∼40% smaller both 24 h and 30 d after stroke than infarcts in macaques that received placebo. When final infarct sizes were normalized to initial sizes to account for variations among individuals, infarct sizes were reduced by 55% at 24 h and 70% at 30 d by treatment with PSD-95 inhibitor. Macaques that received PSD-95 inhibitor also performed better on physical and behavioral tests and had better stroke scores than did macaques that received placebo.

PSD-95 inhibitor has already been tested in a clinical trial to treat ruptured brain aneurysms and shown to be effective in lessening ischemic brain damage and improving neurological scores, making it the first stroke therapy that has demonstrated benefits in humans after testing in primate models.