Sammen Huang1, Haitao Wang1, Ekaterina Turlova1, Ahmed Abussaud1,2, Xiang Ji1,2, Luiz R Britto3, Steven P Miller4, Ana Martinez5, Hong-Shuo Sun1,2, Zhong-Ping Feng1. 1. Department of Physiology, University of Toronto, Toronto, ON, Canada. 2. Department of Surgery, University of Toronto, Toronto, ON, Canada. 3. Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil. 4. Department of Paediatrics, Hospital for Sick Children and University of Toronto, Toronto, ON, Canada. 5. Centro de Investigaciones Biologicas-CSIC, Madrid, Spain.
Abstract
AIMS: Glycogen synthase kinase 3β (GSK-3β) is activated following hypoxic-ischemic (HI) brain injury. TDZD-8 is a specific GSK-3β inhibitor. Currently, the impact of inhibiting GSK-3β in neonatal HI injury is unknown. We aimed to investigate the effect of TDZD-8 following neonatal HI brain injury. METHODS: Unilateral common carotid artery ligation followed by hypoxia was used to induce HI injury in postnatal day 7 mouse pups pretreated with TDZD-8 or vehicle. The infarct volume, whole-brain imaging, Nissl staining, and behavioral tests were used to evaluate the protective effect of TDZD-8 on the neonatal brain and assess functional recovery after injury. Western blot was used to evaluate protein levels of phosphorylated protein kinase B (Akt), GSK-3β, and cleaved caspase-3. Protein levels of cleaved caspase-3, neuronal marker, and glial fibrillary acidic protein were detected through immunohistochemistry. RESULTS: Pretreatment with TDZD-8 significantly reduced brain damage and improved neurobehavioral outcomes following HI injury. TDZD-8 reversed the reduction of phosphorylated Akt and GSK-3β, and the activation of caspase-3 induced by hypoxia-ischemia. In addition, TDZD-8 suppressed apoptotic cell death and reduced reactive astrogliosis. CONCLUSION: TDZD-8 has the therapeutic potential for hypoxic-ischemic brain injury in neonates. The neuroprotective effect of TDZD-8 appears to be mediated through its antiapoptotic activity and by reducing astrogliosis.
AIMS: Glycogen synthase kinase 3β (GSK-3β) is activated following hypoxic-ischemic (HI) brain injury. TDZD-8 is a specific GSK-3β inhibitor. Currently, the impact of inhibiting GSK-3β in neonatal HI injury is unknown. We aimed to investigate the effect of TDZD-8 following neonatal HI brain injury. METHODS: Unilateral common carotid artery ligation followed by hypoxia was used to induce HI injury in postnatal day 7 mouse pups pretreated with TDZD-8 or vehicle. The infarct volume, whole-brain imaging, Nissl staining, and behavioral tests were used to evaluate the protective effect of TDZD-8 on the neonatal brain and assess functional recovery after injury. Western blot was used to evaluate protein levels of phosphorylated protein kinase B (Akt), GSK-3β, and cleaved caspase-3. Protein levels of cleaved caspase-3, neuronal marker, and glial fibrillary acidic protein were detected through immunohistochemistry. RESULTS: Pretreatment with TDZD-8 significantly reduced brain damage and improved neurobehavioral outcomes following HI injury. TDZD-8 reversed the reduction of phosphorylated Akt and GSK-3β, and the activation of caspase-3 induced by hypoxia-ischemia. In addition, TDZD-8 suppressed apoptotic cell death and reduced reactive astrogliosis. CONCLUSION:TDZD-8 has the therapeutic potential for hypoxic-ischemic brain injury in neonates. The neuroprotective effect of TDZD-8 appears to be mediated through its antiapoptotic activity and by reducing astrogliosis.
Authors: F Van Bel; M Shadid; R M Moison; C A Dorrepaal; J Fontijn; L Monteiro; M Van De Bor; H M Berger Journal: Pediatrics Date: 1998-02 Impact factor: 7.124
Authors: Ekaterina Turlova; Raymond Wong; Baofeng Xu; Feiya Li; Lida Du; Steven Habbous; F David Horgen; Andrea Fleig; Zhong-Ping Feng; Hong-Shuo Sun Journal: Transl Stroke Res Date: 2020-05-19 Impact factor: 6.800