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

Zhihua Huang1,2 • Zhengwei Luo1,2 • Andrea Ovcjak1 • Jiangfan Wan1,2 • Nai-hong Chen3 • Wenhui Hu4 • Hong-Shuo Sun1,2,5 • Zhong-Ping Feng1

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

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

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

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

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



    Neuroinflammation is a key contributor to the pathogenic cascades induced by hypoxic-ischemic (HI) insult in the neonatal brain. AD-16 is a novel antiinflammatory 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 OGDinduced 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.




    Neuroinflammation; Neonatal hypoxic-ischemic brain injury; Neuroprotection; AD-16