Journal
BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS
Volume 1860, Issue 10, Pages 2076-2085Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.bbagen.2016.06.027
Keywords
Tideglusib; GSK-3 beta; Neonatal hypoxia-ischemia; Apoptosis; Neuroprotection
Categories
Funding
- National Sciences and Engineering Research Council of Canada [NSERC-RGPIN 402733, NSERC-RGPIN 249962]
- Heart and Stroke Foundation of Canada [G-13-0003069]
Ask authors/readers for more resources
Background: Hypoxia-ischemia is an important cause of brain injury and neurological morbidity in the newborn infants. The activity of glycogen synthase kinase-3 beta (GSK-3 beta) is up-regulated following neonatal stroke. Tideglusib is a GSK-3 beta 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 1 h of hypoxia or sham surgery was performed. HI animals were administered tideglusib (5 mg/kg) or vehicle intraperitoneally 20 min 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-3 beta and protein kinase B (Akt) were detected to identify potentially involved molecules. Results: Tideglusib significantly reduced cerebral infarct volume at both 24 h and 7 days after HI injury. Tideglusib also increased phosphorylated GSK-3 beta(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. (C) 2016 Elsevier B.V. All rights reserved.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available