Treatment of stroke with a PSD-95 inhibitor in the gyrencephalic primate brain

Tat-NR2B9c, a PSD-95 inhibitor, is shown to reduce stroke-induced behavioural and neuroanatomical deficits in cynomolgous macaques when administered in the presence of an ischemic penumbra, suggesting the potential of PSD-95 inhibition as a neuroprotectant strategy for clinical investigation. Limiting brain damage after stroke There are currently no available therapeutic methods for reducing brain damage caused by ischaemia following a stroke, despite decades of research on apparently promising leads discovered in rodent models. Tat-NR2B9c, a compound that interferes with interactions between postsynaptic density protein 95 (PSD-95) and NMDA receptors, thereby reducing neurotoxic signalling, has been shown to be an effective neuroprotectant in cellular and rodent stroke models. Here, Michael Tymianski and colleagues studied the effect of Tat-NR2B9c in cynomolgous monkeys, a closer match than rodents to the human condition. They report that Tat-NR2B9c reduces stroke-induced behavioural and neuroanatomical deficits when administered up to 3 hours after arterial occlusion. These results suggest that PSD-95 inhibition has potential as a neuroprotectant strategy. All attempts at treating strokes by pharmacologically reducing the human brain’s vulnerability to ischaemia have failed, leaving stroke as a leading cause of death, disability and massive socioeconomic loss worldwide 1 . Over decades, research has failed to translate over 1,000 experimental treatments from discovery in cells and rodents to use in humans 2 , 3 , 4 , a scientific crisis that gave rise to the prevailing belief that pharmacological neuroprotection is not feasible or practicable in higher-order brains. To provide a strategy for advancing stroke therapy, we used higher-order gyrencephalic non-human primates, which bear genetic, anatomical and behavioural similarities to humans 5 , 6 and tested neuroprotection by PSD-95 inhibitors—promising compounds that uncouple postsynaptic density protein PSD-95 from neurotoxic signalling pathways 7 , 8 , 9 , 10 . Here we show that stroke damage can be prevented in non-human primates in which a PSD-95 inhibitor is administered after stroke onset in clinically relevant situations. This treatment reduced infarct volumes as gauged by magnetic resonance imaging and histology, preserved the capacity of ischaemic cells to maintain gene transcription in genome-wide screens of ischaemic brain tissue, and significantly preserved neurological function in neurobehav