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Updated: May 22, 2026
Modeling Encephalopathy of Prematurity Using Prenatal Hypoxia-ischemia with Intra-amniotic Lipopolysaccharide in Rats
Published on: November 20, 2015
Involvement of the Akt/GSK-3β/CRMP-2 pathway in axonal injury after hypoxic-ischemic brain damage in neonatal rat
1Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu, Sichuan 610041, PR China.
Abstract:
Akt has been demonstrated as a survival kinase in brain after hypoxia-ischemia (HI). Previous studies have shown that glycogen synthase kinase-3β (GSK-3β)/collapsin response mediator protein 2 (CRMP-2) signaling pathway could be regulated by Akt for axonal-dendritic polarity. CRMP-2 is associated also with microtubule-mediated trafficking. However, whether Akt could regulate GSK-3β/CRMP-2 pathway and the possible effects of this regulation is unclear in developing brain after HI. In this study, we detected the expression of total and phosphorylated Akt, GSK-3β, and CRMP-2, as well as the axonal injury marker amyloid precursor protein (APP) by utilizing an HI model in postnatal 10-day rats. Axonal loss was determined by Bielschowsky silver impregnation, and histological injury was evaluated by hematoxylin and eosin (H&E) staining. We found that the phosphorylation of Akt was accompanied by phosphorylation of GSK-3β and dephosphorylation of CRMP-2 after HI. Furthermore, Akt inhibition significantly decreased the phosphorylation of GSK-3β and dephosphorylation of CRMP-2. Moreover, the down-regulation of dephosphorylated CRMP-2 was associated with increased axonal injury (increased APP expression and axonal loss). Our findings suggest that the Akt/GSK-3β/CRMP-2 pathway mediates axonal injury in neonatal rat brain after HI.
Insights
Akt signaling protects the developing brain from hypoxia-ischemia (HI) injury by regulating the GSK-3β/CRMP-2 pathway. This pathway
Area of Science:
- Neuroscience
- Molecular Biology
- Developmental Biology
Background:
- Akt acts as a survival kinase in the brain following hypoxia-ischemia (HI).
- The Akt pathway is known to regulate glycogen synthase kinase-3β (GSK-3β)/collapsin response mediator protein 2 (CRMP-2) signaling, impacting axonal-dendritic polarity and microtubule trafficking.
Purpose of the Study:
- To investigate whether Akt regulates the GSK-3β/CRMP-2 pathway in the developing brain after HI.
- To determine the effects of this Akt-mediated regulation on axonal injury following HI.
Main Methods:
- Established a hypoxia-ischemia (HI) model in postnatal 10-day-old rats.
- Assessed the expression of total and phosphorylated Akt, GSK-3β, and CRMP-2.
- Measured axonal injury markers, including amyloid precursor protein (APP), axonal loss (Bielschowsky silver impregnation), and histological damage (H&E staining).
Main Results:
- HI induced Akt phosphorylation, which correlated with GSK-3β phosphorylation and CRMP-2 dephosphorylation.
- Akt inhibition reduced GSK-3β phosphorylation and CRMP-2 dephosphorylation.
- Reduced dephosphorylated CRMP-2 levels were associated with increased axonal injury, evidenced by elevated APP expression and axonal loss.
Conclusions:
- The Akt/GSK-3β/CRMP-2 signaling pathway plays a crucial role in mediating axonal injury in the neonatal rat brain after HI.
- Understanding this pathway offers potential therapeutic targets for neonatal brain injury.
