Haitao Wang1, Sammen Huang2, Kuipo Yan1, Xiaoyan Fang2, Ahmed Abussaud2, Ana Martinez3, Hong-Shuo Sun4, Zhong-Ping Feng5. 1. Department of Physiology, University of Toronto, Toronto, Ontario, Canada. 2. Department of Physiology, University of Toronto, Toronto, Ontario, Canada; Department of Surgery, University of Toronto, Toronto, Ontario, Canada. 3. Centro de Investigaciones Biologicas-CSIC, Madrid, Spain. 4. Department of Physiology, University of Toronto, Toronto, Ontario, Canada; Department of Surgery, University of Toronto, Toronto, Ontario, Canada. Electronic address: hss.sun@utoronto.ca. 5. Department of Physiology, University of Toronto, Toronto, Ontario, Canada. Electronic address: zp.feng@utoronto.ca.
Abstract
BACKGROUND: Hypoxia-ischemia is an important cause of brain injury and neurological morbidity in the newborn infants. The activity of glycogen synthase kinase-3β (GSK-3β) is up-regulated following neonatal stroke. Tideglusib is a GSK-3β inhibitor which has neuroprotective effects against neurodegenerative diseases in clinical trials. However, the effect of tideglusib on hypoxic-ischemic (HI) brain injury in neonates is still unknown. METHODS: Postnatal day 7 (P7) mouse pups subjected to unilateral common carotid artery ligation followed by 1h of hypoxia or sham surgery was performed. HI animals were administered tideglusib (5mg/kg) or vehicle intraperitoneally 20min prior to the onset of ischemia. The brain infarct volume and whole brain images, were used in conjunction with Nissl staining to evaluate the protective effects of tideglusib. Protein levels of glial fibrillary acidic protein (GFAP), Notch1, cleaved caspase-3/9, phosphorylated signal transducer and activator of transcription 3 (STAT3), GSK-3β and protein kinase B (Akt) were detected to identify potentially involved molecules. RESULTS: Tideglusib significantly reduced cerebral infarct volume at both 24h and 7days after HI injury. Tideglusib also increased phosphorylated GSK-3β(Ser9) and Akt(Ser473), and reduced the expression of GFAP and p-STAT3(Tyr705). In addition, pretreatment with tideglusib also enhanced the protein level of Notch1. Moreover, tideglusib reduced the cleavage of pro-apoptotic signal caspase proteins, including caspase 3 and caspase 9 following HI. CONCLUSION: These results indicate that tideglusib shows neuroprotection against hypoxic-ischemic brain injury in neonatal mice. GENERAL SIGNIFICANCE: Tideglusib is a potential compound for the prevention or treatment of hypoxic-ischemic brain injury in neonates.
BACKGROUND:Hypoxia-ischemia is an important cause of brain injury and neurological morbidity in the newborn infants. The activity of glycogen synthase kinase-3β (GSK-3β) is up-regulated following neonatal stroke. Tideglusib is a GSK-3β inhibitor which has neuroprotective effects against neurodegenerative diseases in clinical trials. However, the effect of tideglusib on hypoxic-ischemic (HI) brain injury in neonates is still unknown. METHODS: Postnatal day 7 (P7) mouse pups subjected to unilateral common carotid artery ligation followed by 1h of hypoxia or sham surgery was performed. HI animals were administered tideglusib (5mg/kg) or vehicle intraperitoneally 20min prior to the onset of ischemia. The brain infarct volume and whole brain images, were used in conjunction with Nissl staining to evaluate the protective effects of tideglusib. Protein levels of glial fibrillary acidic protein (GFAP), Notch1, cleaved caspase-3/9, phosphorylated signal transducer and activator of transcription 3 (STAT3), GSK-3β and protein kinase B (Akt) were detected to identify potentially involved molecules. RESULTS:Tideglusib significantly reduced cerebral infarct volume at both 24h and 7days after HI injury. Tideglusib also increased phosphorylated GSK-3β(Ser9) and Akt(Ser473), and reduced the expression of GFAP and p-STAT3(Tyr705). In addition, pretreatment with tideglusib also enhanced the protein level of Notch1. Moreover, tideglusib reduced the cleavage of pro-apoptotic signal caspase proteins, including caspase 3 and caspase 9 following HI. CONCLUSION: These results indicate that tideglusib shows neuroprotection against hypoxic-ischemic brain injury in neonatal mice. GENERAL SIGNIFICANCE: Tideglusib is a potential compound for the prevention or treatment of hypoxic-ischemic brain injury in neonates.