• Lirong Liang, Rougang Xie, Rui Lu, Ruixue Ma, Xiaoxia Wang, Fengjuan Wang, Bing Liu, Shengxi Wu, Yazhou Wang, and Hui Zhang.
• State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi Engineering Research, Center for Dental Materials and Advanced Manufacture, Department of Anethesiology, School of Stomatology, Fourth Military Medical University, Xi'an, Shaanxi, P. R. China.
• J. Neurochem. 2020 Aug 1; 154 (4): 372-388.

AbstractSevoflurane is one of the most widely used anesthetics with recent concerns rising about its pediatric application. The synaptic toxicity and mechanisms underlying its long-term cognition impairment remain unclear. In this study, we investigated the expression and roles of homeodomain interacting protein kinase 2 (HIPK2), a stress activating kinase involved in neuronal survival and synaptic plasticity, and its downstream c-Jun N-terminal kinase (JNK)/c-Jun signaling in the long-term toxicity of neonatal Sevoflurane exposure. Our data showed that neonatal Sevoflurane exposure results in impairment of memory, enhancement of anxiety, less number of excitatory synapses and lower levels of synaptic proteins in the hippocampus of adult rats without significant changes of hippocampal neuron numbers. Up-regulation of HIPK2 and JNK/c-Jun was observed in hippocampal granular neurons shortly after Sevoflurane exposure and persisted to adult. 5-((6-Oxo-5-(6-(piperazin-1-yl)pyridin-3-yl)-1,6-dihydropyridin-3-yl)methylene)thiazolidine-2,4-dione trifluoroacetate, antagonist of HIPK2, could significantly rescue the cognition impairment, decrease in long-term potentiation, reduction in spine density and activation of JNK/c-Jun induced by Sevoflurane. JNK antagonist SP600125 partially restored synapse development and cognitive function without affecting the expression of HIPK2. These data, in together, revealed a novel role of HIPK2-JNK/c-Jun signaling in the long-term synaptic toxicity and cognition impairment of neonatal Sevoflurane exposure, indicating HIPK2-JNK/c-Jun cascade as a potential target for reducing the synaptic toxicity of Sevoflurane. Cover Image for this issue: doi: 10.1111/jnc.14757.© 2019 The Authors. Journal of Neurochemistry published by John Wiley & Sons Ltd on behalf of International Society for Neurochemistry.

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