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Cell Physiol Biochem. 2014;33(6):1715-32. doi: 10.1159/000362953. Epub 2014 May 20.

Repeated administration of ketamine can induce hippocampal neurodegeneration and long-term cognitive impairment via the ROS/HIF-1α pathway in developing rats.

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1
Department of Anesthesiology and Critical Care Medicine, Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 639 Zhi Zao Ju Road, Shanghai 200011, China.

Abstract

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.

PMID:
24923288
DOI:
10.1159/000362953
[Indexed for MEDLINE]
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