Effects of dexmedetomidine on ferroptosis and neurological function of neonatal rats with hypoxic-ischemic brain damage through the Nrf2/Gpx4 signaling pathway
Objective To study the effects of dexmedetomidine(DEX)on ferroptosis and neurological function of neonatal rats with hypoxic-ischemic brain damage(HIBD)through the nuclear factor E2-related factor 2(Nrf2)/glutathione peroxidase 4(Gpx4)signaling pathway.Methods A HIBD model was created in neonatal rats.They were randomly assigned into model group,DEX group(100µg/kg DEX)and DEX+Nrf2 inhibitor group(10Oμg/kg DEX+Nrf2 inhibitor brucebitol 2mg/kg),with 12 rats in each group.Another 12 neonatal rats were selected as control group.Rats in the control group and model group were intraperitoneally injected with the same volume of normal saline.Neurological deficit score(NDS)was graded to evaluate rat neurological function.An amino acid automatic analyzer was used to measure the levels of glutamate(Glu)and γ-aminobutyric acid(GABA)in the hippocampus.Nissl staining was performed to measure the morphology of neurons in the hippocampus.Enzyme-linked immunosorbent assay(ELISA)was performed to measure the levels of interleukin-6(IL-6),tumor necrosis factor-α(TNF-α)and neuron-specific enolase(NSE)in the hippocampus.Commercial kits were used to measure the contents of malondialdehyde(MDA),glutathione(GSH)and iron in the hippocampus.Western blotting was performed to measure the protein expressions of Nrf2,heme-oxygenase(HO)-1,Gpx4,and cystine/glutamate antiporter(xCT)in the hippocampus.Results Compared with those of the control group,rats in the model group presented an abnormal morphology of hippocampal neurons,varying length of disorderly arranged ventral neurons with dorsal detachment in some neurons,significantly higher NDS score and the contents of Glu,IL-6,TNF-α,NSE,MDA and iron in the hippocampus(P＜0.05),but significantly lower contents of GABA and GSH,and protein levels of Nrf2,HO-1,Gpx4,and xCT(P＜0.05).Compared with those of the model group,rats in the DEX group had relatively intact neurons in the hippocampus,well arranged axons in the ventral neurons,significantly lower NDS score and the contents of Glu,IL-6,TNF-α,NSE,MDA and iron in the hippocampus(P＜0.05),but significantly higher contents of GABA and GSH,and protein levels of Nrf2,HO-1,Gpx4,and xCT(P＜0.05).Nrf2 inhibitor could reduce the protective effect of DEX on nerve injury in neonatal rats with HIBD(P＜0.05).Conclusion DEX alleviates nerve injury in neonatal rats with HIBD by inhibiting ferroptosis via activating the Nrf2/Gpx4 signaling pathway.
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