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

Abstract

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 worldwide1. Over decades, research has failed to translate over 1,000 experimental treatments from discovery in cells and rodents to use in humans2,3,4, 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 humans5,6 and tested neuroprotection by PSD-95 inhibitors—promising compounds that uncouple postsynaptic density protein PSD-95 from neurotoxic signalling pathways7,8,9,10. 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 neurobehavioural assays. The degree of tissue neuroprotection by magnetic resonance imaging corresponded strongly to the preservation of neurological function, supporting the intuitive but unproven dictum that integrity of brain tissue can reflect functional outcome. Our findings establish that tissue neuroprotection and improved functional outcome after stroke is unequivocally achievable in gyrencephalic non-human primates treated with PSD-95 inhibitors. Efforts must ensue to translate these findings to humans.

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Figure 1: Treatment with Tat-NR2B9c attenuates infarct volume in NHPs subjected to MCAO(−)p.
Figure 2: Treatment with Tat-NR2B9c preserves capacity for transcription in NHPs subjected to stroke.
Figure 3: Treatment with Tat-NR2B9c at 60 min improves MRI and functional outcome after a 4.5-h MCAO(−)p.
Figure 4: Treatment with Tat-NR2B9c at 3 h improves MRI and functional outcome after a 3.5-h MCAO(+)p.

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Primary accessions

Gene Expression Omnibus

Data deposits

Microarray data are deposited in National Center for Biotechnology Information (NCBI) Gene Expression Omnibus under accession number GSE35589.

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Acknowledgements

This work was supported by grants to M.T. from the Canadian Stroke Network and the Heart and Stroke Foundation of Ontario, grant NA 6988. D.J.C. is a recipient of a Canadian Stroke Network postdoctoral research fellowship. M.T. is a Canada Research Chair (Tier 1) in Translational Stroke Research. We thank M. Madden, B. Maloo, A. Goldstein, B. Madeira, W. Foltz and Z. Lu for assistance. We thank M. Salter and M. Hill for a review of the manuscript.

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D.C. and M.T. performed the experimental procedures, collected and analysed the data and drafted the manuscript. L.T. performed experimental procedures and data collection.

Corresponding author

Correspondence to Michael Tymianski.

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Competing interests

M.T. is president of NoNO Inc., a biotechnology company founded to develop PSD-95 inhibitors discovered in his research laboratory.

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This file contains Supplementary Figures 1-6 with legends, Supplementary Methods, a Supplementary Discussion, Supplementary Tables 1-4 and Supplementary References. (PDF 5966 kb)

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Cook, D., Teves, L. & Tymianski, M. Treatment of stroke with a PSD-95 inhibitor in the gyrencephalic primate brain. Nature 483, 213–217 (2012). https://doi.org/10.1038/nature10841

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