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Neuroprotective Effects of a PSD-95 Inhibitor in Neonatal Hypoxic-Ischemic Brain Injury

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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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References

  1. Nelson KB (2007) Perinatal ischemic stroke. Stroke 38:742–745

    Article  PubMed  Google Scholar 

  2. Vannucci SJ (2007) Cerebral ischemia and the developing brain: introduction. Stroke 38:723

    Article  Google Scholar 

  3. Vannucci SJ, Hagberg H (2004) Hypoxia-ischemia in the immature brain. J Exp Biol 207:3149–3154

    Article  CAS  PubMed  Google Scholar 

  4. Kruse M, Michelsen SI, Flachs EM, Bronnum-Hansen H, Madsen M, Uldall P (2009) Lifetime costs of cerebral palsy. Dev Med Child Neurol 51:622–628

    Article  PubMed  Google Scholar 

  5. Aarts M, Liu Y, Liu L, Besshoh S, Arundine M, Gurd JW, Wang YT, Salter MW et al (2002) Treatment of ischemic brain damage by perturbing NMDA receptor-PSD-95 protein interactions. Science 298:846–850

    Article  CAS  PubMed  Google Scholar 

  6. Stroke Therapy Academic Industry Roundtable (STAIR) (1999) Recommendations for standards regarding preclinical neuroprotective and restorative drug development. Stroke 30:2752–2758

    Article  Google Scholar 

  7. Sun HS, Doucette TA, Liu Y, Fang Y, Teves L, Aarts M, Ryan CL, Bernard PB et al (2008) Effectiveness of PSD95 inhibitors in permanent and transient focal ischemia in the rat. Stroke 39:2544–2553

    Article  CAS  PubMed  Google Scholar 

  8. Cook DJ, Teves L, Tymianski M (2012) Treatment of stroke with a PSD-95 inhibitor in the gyrencephalic primate brain. Nature 483:213–217

    Article  CAS  PubMed  Google Scholar 

  9. Hill MD, Martin RH, Mikulis D, Wong JH, Silver FL, Terbrugge KG, Milot G, Clark WM et al (2012) Safety and efficacy of NA-1 in patients with iatrogenic stroke after endovascular aneurysm repair (ENACT): a phase 2, randomised, double-blind, placebo-controlled trial. Lancet Neurol 11:942–950

    Article  CAS  PubMed  Google Scholar 

  10. Rice JE III, Vannucci RC, Brierley JB (1981) The influence of immaturity on hypoxic-ischemic brain damage in the rat. Ann Neurol 9:131–141

    Article  PubMed  Google Scholar 

  11. Levine S (1960) Anoxic-ischemic encephalopathy in rats. Am J Pathol 36:1–17

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Sun HS, Xu B, Chen W, Xiao A, Turlova E, Alibraham A, Barszczyk A, Bae CY et al (2015) Neuronal K(ATP) channels mediate hypoxic preconditioning and reduce subsequent neonatal hypoxic-ischemic brain injury. Exp Neurol 263:161–171

    Article  CAS  PubMed  Google Scholar 

  13. Alibrahim A, Zhao LY, Bae CY, Barszczyk A, Lf SC, Wang GL, Sun HS (2013) Neuroprotective effects of volume-regulated anion channel blocker DCPIB on neonatal hypoxic-ischemic injury. Acta Pharmacol Sin 34:113–118

    Article  CAS  PubMed  Google Scholar 

  14. Chen W, Xu B, Xiao A, Liu L, Fang X, Liu R, Turlova E, Barszczyk A et al (2015) TRPM7 inhibitor carvacrol protects brain from neonatal hypoxic-ischemic injury. Mol Brain 8:11

    Article  PubMed  PubMed Central  Google Scholar 

  15. Xiao AJ, Chen W, Xu B, Liu R, Turlova E, Barszczyk A, Sun CL, Liu L et al (2015) Marine compound xyloketal B reduces neonatal hypoxic-ischemic brain injury. Mar Drugs 13:29–47

    Article  Google Scholar 

  16. Shen Y, Isaacson RL, Smotherman WP (1991) The behavioral and anatomical effects of prenatal umbilical cord clamping in the rat and their alteration by the prior maternal administration of nimodipine. Restor Neurol Neurosci 3:11–22

    CAS  PubMed  Google Scholar 

  17. Sanches EF, Arteni NS, Spindler C, Moyses F, Siqueira IR, Perry ML, Netto CA (2012) Effects of pre- and postnatal protein malnutrition in hypoxic-ischemic rats. Brain Res 1438:85–92

    Article  CAS  PubMed  Google Scholar 

  18. Liu XH, Yan H, Xu M, Zhao YL, Li LM, Zhou XH, Wang MX, Ma L (2013) Hyperbaric oxygenation reduces long-term brain injury and ameliorates behavioral function by suppression of apoptosis in a rat model of neonatal hypoxia-ischemia. Neurochem Int 62:922–930

    Article  CAS  PubMed  Google Scholar 

  19. Sun HS, Jackson MF, Martin LJ, Jansen K, Teves L, Cui H, Kiyonaka S, Mori Y et al (2009) Suppression of hippocampal TRPM7 protein prevents delayed neuronal death in brain ischemia. Nat Neurosci 12:1300–1307

    Article  CAS  PubMed  Google Scholar 

  20. Sidhu RS, Tuor UI, Del Bigio MR (1997) Nuclear condensation and fragmentation following cerebral hypoxia-ischemia occurs more frequently in immature than older rats. Neurosci Lett 223:129–132

    Article  CAS  PubMed  Google Scholar 

  21. Manabat C, Han BH, Wendland M, Derugin N, Fox CK, Choi J, Holtzman DM, Ferriero DM et al (2003) Reperfusion differentially induces caspase-3 activation in ischemic core and penumbra after stroke in immature brain. Stroke 34:207–213

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Zhao H, Sapolsky RM, Steinberg GK (2006) Phosphoinositide-3-kinase/akt survival signal pathways are implicated in neuronal survival after stroke. Mol Neurobiol 34:249–270

    Article  CAS  PubMed  Google Scholar 

  23. Sattler R, Xiong Z, Lu WY, Hafner M, MacDonald JF, Tymianski M (1999) Specific coupling of NMDA receptor activation to nitric oxide neurotoxicity by PSD-95 protein. Science 284:1845–1848

    Article  CAS  PubMed  Google Scholar 

  24. Bratane BT, Cui H, Cook DJ, Bouley J, Tymianski M, Fisher M (2011) Neuroprotection by freezing ischemic penumbra evolution without cerebral blood flow augmentation with a postsynaptic density-95 protein inhibitor. Stroke 42:3265–3270

    Article  CAS  PubMed  Google Scholar 

  25. Davis SM, Lees KR, Albers GW, Diener HC, Markabi S, Karlsson G, Norris J (2000) Selfotel in acute ischemic stroke: possible neurotoxic effects of an NMDA antagonist. Stroke 31:347–354

    Article  CAS  PubMed  Google Scholar 

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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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Correspondence to Zhong-Ping Feng or Hong-Shuo Sun.

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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

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