Sevoflurane‑induced neurotoxicity is driven by OXR1 post‑transcriptional downregulation involving hsa‑miR‑302e

Yang,Leilei; Shen,Qian; Xia,Yanqiong; Lei,Xueheng; Peng,Jian

doi:10.3892/mmr.2018.9442

Sevoflurane‑induced neurotoxicity is driven by OXR1 post‑transcriptional downregulation involving hsa‑miR‑302e

Authors:
- Leilei Yang
- Qian Shen
- Yanqiong Xia
- Xueheng Lei
- Jian Peng
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Affiliations: Department of Anesthesiology, Tongren Hospital of Wuhan University (Wuhan Third Hospital), Wuhan, Hubei 430060, P.R. China
Published online on: September 3, 2018 https://doi.org/10.3892/mmr.2018.9442
Pages: 4657-4665

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Abstract

Sevoflurane is a common anesthetic agent used in surgical settings and previous studies have indicated that it exerts a neurotoxic effect. However, the molecular mechanism underlying this side effect is unknown. In addition, the human microRNA‑302 (hsa‑miR‑302) family members have been reported to be involved in neuronal cell development and biology. Thus, the present study aimed to investigate the potential implication of hsa‑miR‑302e in the sevoflurane‑induced cytotoxicity on human hippocampal cells (HN‑h). HN‑h cells were transfected with hsa‑miR‑302e mimic, hsa‑miR‑302e inhibitor or negative controls and subsequently exposed to different concentrations of sevoflurane. An MTT assay was used to assess the cytotoxicity of sevoflurane on HN‑h cells. Cell apoptosis was determined by flow cytometry. The levels of lactate dehydrogenase release, reactive oxygen species, lipid peroxidation and intracellular calcium (Ca2+) were additionally detected. Reverse transcription‑quantitative polymerase chain reaction and western blotting were conducted to determine mRNA and protein expression, respectively. A luciferase assay was performed for validating the targeting of OXR1 by hsa‑miR‑302e. The results indicated that sevoflurane induced a decrease in cell viability, malondialdehyde and reactive oxygen species production, lactate dehydrogenase release, intracellular Ca2+ production, calcium/calmodulin‑dependent protein kinase II phosphorylation and apoptosis. In addition, treatment with sevoflurane induced the expression of hsa‑miR‑302e while the expression of its target, oxidation resistance gene 1 (OXR1), was significantly downregulated. Inhibition of hsa‑miR‑302e expression protected neuronal cells from sevoflurane cytotoxicity. Mechanistic studies demonstrated that OXR1 was a direct target of hsa‑miR‑302e. Furthermore, the overexpression of OXR1 abolished the effect of sevoflurane on neuronal cells. The results of the present study indicated that sevoflurane exerts its neurotoxic effect by regulating the hsa‑miR‑302e/OXR1 axis. Therefore, the manipulation of the hsa‑miR‑302e/OXR1 pathway will be useful for preventing sevoflurane‑induced neurotoxicity.

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