Abstract
The postsynaptic density-95 inhibitor NA-1 uncouples NMDA glutamate receptors from downstream neurotoxic signaling pathways without affecting normal glutamate receptor function. NA-1 attenuates NMDA receptor-mediated neuronal cell death after stroke in multiple models and species. However, its efficacy in providing neuroprotection in models of neonatal hypoxic-ischemic brain injury has not yet been tested. In this study, a modified version of the Rice-Vannucci method for the induction of neonatal hypoxic-ischemic brain injury was performed on postnatal day 7 mouse pups. Animals received a single dose of NA-1 intraperitoneally either before or after right common carotid artery occlusion. All experiments were performed in a blinded manner. Infarct volumes were measured 1 and 7 days after the injury, while behavioral tests were conducted 1, 3, and 7 days after injury. Administration of NA-1 before right common carotid artery occlusion or immediately after ischemia significantly reduced infarct volume and improved neurobehavioral outcomes 1, 3, and 7 days post-injury. The neuroprotection and improvement in neurobehavioral outcomes conferred by NA-1 in this mouse neonatal hypoxic-ischemic injury model imply that NA-1 will be effective in reducing neonatal stroke damage and thus could potentially serve as a therapeutic drug for prevention or treatment of neonatal stroke.
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Acknowledgments
Supported by grants to HSS from the Heart and Stroke Foundation of Canada (G-13-0003069) and the Scottish Rite Charitable Foundation of Canada (#12104), and to ZPF from the National Sciences and Engineering Research Council of Canada (NSERC-249962-09). BX, AJX, RL, and LL were supported by China Scholarship Council Fellowships; ET was supported by a CIHR-CGS-M studentship, and AB and CLFS were supported by Ontario Graduate Scholarships. ZPF is a recipient of a New Investigator Award from the Heart and Stroke Foundation of Canada.
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MT is the President and CEO of NoNO Inc, a biotechnology company developed to translate neuroprotectants discovered through cellular and molecular research in his laboratory to patients. The remaining authors declare that they have no conflicts of interest.
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Baofeng Xu, Ai-Jiao Xiao and Wenliang Chen contributed equally to this work.
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Xu, B., Xiao, AJ., Chen, W. et al. Neuroprotective Effects of a PSD-95 Inhibitor in Neonatal Hypoxic-Ischemic Brain Injury. Mol Neurobiol 53, 5962–5970 (2016). https://doi.org/10.1007/s12035-015-9488-4
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DOI: https://doi.org/10.1007/s12035-015-9488-4