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Neuroprotective Effects of AG490 in Neonatal Hypoxic-Ischemic Brain Injury

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Abstract

In infants and children, neonatal hypoxic-ischemic (HI) brain injury represents a major cause of chronic neurological morbidity. The transient receptor potential melastatin 2 (TRPM2), a non-selective cation channel that conducts calcium, can mediate neuronal death following HI brain injury. An important endogenous activator of TRPM2 is H2O2, which has previously been reported to be upregulated in the neonatal brain after hypoxic ischemic injury. Here, incorporating both in vitro (H2O2-induced neuronal cell death model) and in vivo (mouse HI brain injury model) approaches, we examined the effects of AG490, which can inhibit the H2O2-induced TRPM2 channel. We found that AG490 elicited neuroprotective effects. We confirmed that AG490 reduced H2O2-induced TRPM2 currents. Specifically, application of AG490 to neurons ameliorated H2O2-induced cell injury in vitro. In addition, AG490 administration reduced brain damage and improved neurobehavioral performance following HI brain injury in vivo. The neuroprotective benefits of AG490 suggest that pharmacological inhibition of H2O2-activated TRPM2 currents can be exploited as a potential therapeutic strategy to treat HI-induced neurological complications.

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Acknowledgments

We also thank S Huang and W Chen for their technical assistance.

Funding

This study is supported by grants to HSS from Natural Sciences and Engineering Research Council of Canada (NSERC) Discovery Grants (RGPIN-2016-04574) and to ZPF from the National Sciences and Engineering Research Council of Canada (RGPIN-2014-06471).

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  1. Feiya Li, Raymond Wong and Zhengwei Luo contributed equally to this work.

Authors and Affiliations

  1. Department of Surgery, Faculty of Medicine, University of Toronto, 1 King’s College Circle, Toronto, Ontario, M5S 1A8, Canada

    Feiya Li, Raymond Wong, Zhengwei Luo, Lida Du, Ekaterina Turlova & Hong-Shuo Sun

  2. Department of Physiology, Faculty of Medicine, University of Toronto, 1 King’s College Circle, Toronto, Ontario, M5S 1A8, Canada

    Feiya Li, Raymond Wong, Zhengwei Luo, Lida Du, Ekaterina Turlova, Zhong-Ping Feng & Hong-Shuo Sun

  3. Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil

    Luiz R. G. Britto

  4. Department of Pharmacology and Toxicology, Faculty of Medicine, University of Toronto, Toronto, Ontario, M5S 1A8, Canada

    Hong-Shuo Sun

  5. Institute of Medical Science, Faculty of Medicine, University of Toronto, Toronto, Ontario, M5S 1A8, Canada

    Hong-Shuo Sun

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  1. Feiya Li
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Li, F., Wong, R., Luo, Z. et al. Neuroprotective Effects of AG490 in Neonatal Hypoxic-Ischemic Brain Injury. Mol Neurobiol 56, 8109–8123 (2019). https://doi.org/10.1007/s12035-019-01656-z

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