Repeated Administration of Ketamine can Induce Hippocampal Neurodegeneration and Long-Term Cognitive Impairment via the ROS/HIF-1α Pathway in Developing Rats

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)-1 alpha(YC-1), ketamine+inhibitor of reactive oxygen species(ROS) (L-carnitine) or ketamine+Ca2+ 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- 1 alpha 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- 1 alpha, 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-1 alpha 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 keta mine-induced neurodegeneration in neonatal rats, followed by long-term cognitive deficits, might be mediated via the ROS/HIF-1 alpha pathway. Copyright (C) 2014 S. Karger AG, Basel