Cell Physiol Biochem, May 2014.
Yan J, Huang Y, Lu Y, Chen J, Jiang H..
Background: Recent animal experiments have suggested that ketamine administration during development might induce widespread neurodegeneration and long-term cognitive deficits. The underlying mechanism is not fully understood.
Methods: Immature rat hippocampal neurons and newborn rats underwent repeated exposure to ketamine, ketamine+inhibitor of hypoxia-inducible factor (HIF)-1α(YC-1), ketamine+inhibitor of reactive oxygen species(ROS) (L-carnitine) or ketamine+Ca(2+) blocker(nimodipine). Apoptosis of the hippocampal neurons was analyzed by TUNEL and flow cytometry. Intracellular ROS were measured using 2′,7′-dichlorofluorescein diacetate. The expression of HIF- 1α and apoptosis-related proteins was analyzed by western blot or qPCR. As these rats grew, behavioral tests were performed to evaluate cognitive function.
Results: The apoptotic rate in the ketamine group was significantly higher than that in the other groups, and the intracellular ROS levels in the ketamine and ketamine+YC-1 groups were higher than those in the other groups. The expression of HIF- 1α, p53, BNIP3 and cleaved caspase-3 proteins increased, and the ratio of Bcl-2/Bax decreased in the ketamine group. The transcriptional levels of HIF-1α in the ketamine and ketamine+YC-1 groups were higher than those in the other groups. Cognitive deficits were found only in the ketamine group.
Conclusion: We suggest that ketamine-induced neurodegeneration in neonatal rats, followed by long-term cognitive deficits, might be mediated via the ROS/HIF-1α pathway.
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