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Arch Med Sci. 2015 Dec 10;11(6):1296-302. doi: 10.5114/aoms.2015.56355. Epub 2015 Dec 11.

The role of TNF-α in regulating ketamine-induced hippocampal neurotoxicity.

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1
Department of Anesthesia, Zhejiang Hospital, Hangzhou, Zhejiang, China.

Abstract

INTRODUCTION:

Ketamine is commonly used in pediatric anesthesia but recent studies have shown that it could induce neurotoxicity in the developing brain. The inflammatory cytokine, tumor necrosis factor α (TNF-α) is involved in the pathogenesis of various types of neurodegenerations. In the present study, we examined whether TNF-α may regulate ketamine-induced neurotoxicity in the hippocampus of neonatal mouse.

MATERIAL AND METHODS:

The in vitro organotypic culture of hippocampal slices was used to investigate the gain-of-function and loss-of-function effect of TNF-α modulation on ketamine-induced hippocampal neurotoxicity. Also, western blotting analysis was used to examine the relative pathways associated with TNF-α modulation. In the in vivo Morris water maze test, TNF-α was genetically silenced to see if memory function was improved after anesthesia-induced memory impairment.

RESULTS:

In in vitro experiments, adding TNF-α enhanced (112.99 ±5.4%, p = 0.015), whereas knocking down TNF-α ameliorated (46.8 ±11.6%, p = 0.003) ketamine-induced apoptosis in hippocampal CA1 neurons in the organotypic culture. Western blotting showed that addition of TNF-α reduced (67.1 ±3.7%, p = 0.022), whereas downregulation of TNF-α increased (126.87 ±8.5%, p = 0.004) the phosphorylation of PKC-ERK pathway in ketamine-treated hippocampus. In in vivo experiments, genetically silencing TNF-α markedly improved the ketamine-induced memory impairment through Morris water maze test.

CONCLUSIONS:

Our results clearly demonstrated a protective mechanism of down-regulating TNF in ketamine-induced hippocampal neurotoxicity. This study may present a new target for pharmacological intervention to prevent anesthesia-related neurodegeneration in brain.

KEYWORDS:

anesthesia; hippocampus; ketamine; neurotoxicity; tumor necrosis factor-α

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