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AD-16 Protects Against Hypoxic-Ischemic Brain Injury by Inhibiting Neuroinflammation

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Abstract

Neuroinflammation is a key contributor to the pathogenic cascades induced by hypoxic-ischemic (HI) insult in the neonatal brain. AD-16 is a novel anti-inflammatory compound, recently found to exert potent inhibition of the lipopolysaccharide-induced production of pro-inflammatory and neurotoxic mediators. In this study, we evaluated the effect of AD-16 on primary astrocytes and neurons under oxygen-glucose deprivation (OGD) in vitro and in mice with neonatal HI brain injury in vivo. We demonstrated that AD-16 protected against OGD-induced astrocytic and neuronal cell injury. Single dose post-treatment with AD-16 (1 mg/kg) improved the neurobehavioral outcome and reduced the infarct volume with a therapeutic window of up to 6 h. Chronic administration reduced the mortality rate and preserved whole-brain morphology following neonatal HI. The in vitro and in vivo effects suggest that AD-16 offers promising therapeutic efficacy in attenuating the progression of HI brain injury and protecting against the associated mortality and morbidity.

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Acknowledgements

This work was supported by the Canadian Institutes of Health Research (CIHR PJT-153155) to ZPF and a Natural Sciences and Engineering Research Council of Canada Discovery Grant (NSERC RGPIN-2016-04574) to HSS.

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Author notes

  1. Zhihua Huang and Zhengwei Luo have contributed equally to this work.

Authors and Affiliations

  1. Department of Physiology, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, M5S 1A8, Canada

    Zhihua Huang, Zhengwei Luo, Andrea Ovcjak, Jiangfan Wan, Hong-Shuo Sun & Zhong-Ping Feng

  2. Department of Surgery, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, M5S 1A8, Canada

    Zhihua Huang, Zhengwei Luo, Jiangfan Wan & Hong-Shuo Sun

  3. State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Neuroscience Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China

    Nai-hong Chen

  4. Key Laboratory of Molecular Target and Clinical Pharmacology, State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, Guangdong, China

    Wenhui Hu

  5. Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON, M5S 3M2, Canada

    Hong-Shuo Sun

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  1. Zhihua Huang
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Huang, Z., Luo, Z., Ovcjak, A. et al. AD-16 Protects Against Hypoxic-Ischemic Brain Injury by Inhibiting Neuroinflammation. Neurosci. Bull. 38, 857–870 (2022). https://doi.org/10.1007/s12264-021-00816-3

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