[No authors listed]
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 microRNAâ302 (hsaâmiRâ302) 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 hsaâmiRâ302e in the sevofluraneâinduced cytotoxicity on human hippocampal cells (HNâh). HNâh cells were transfected with hsaâmiRâ302e mimic, hsaâmiRâ302e inhibitor or negative controls and subsequently exposed to different concentrations of sevoflurane. An MTT assay was used to assess the cytotoxicity of sevoflurane on HNâh 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 transcriptionâquantitative 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 hsaâmiRâ302e. The results indicated that sevoflurane induced a decrease in cell viability, malondialdehyde and reactive oxygen species production, lactate dehydrogenase release, intracellular Ca2+ production, calcium/calmodulinâdependent protein kinase II phosphorylation and apoptosis. In addition, treatment with sevoflurane induced the expression of hsaâmiRâ302e while the expression of its target, oxidation resistance gene 1 (OXR1), was significantly downregulated. Inhibition of hsaâmiRâ302e expression protected neuronal cells from sevoflurane cytotoxicity. Mechanistic studies demonstrated that OXR1 was a direct target of hsaâmiRâ302e. 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 hsaâmiRâ302e/OXR1 axis. Therefore, the manipulation of the hsaâmiRâ302e/OXR1 pathway will be useful for preventing sevofluraneâinduced neurotoxicity.
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