title: Erythropoietin rescues primary rat cortical neurons from pyroptosis and apoptosis via Erk1/2-Nrf2/Bach1 signal pathway.
abstract: The most commonly used inhalation anesthetics, sevoflurane, is reported to be a risk for development of learning disability. Erythropoietin (EPO) administration might be involved an effective therapy for sevoflurane neurotoxicity. EPO-EPO receptor-extracellular signal-related kinases 1/2 (Erk1/2) signal pathway plays a pivotal role in the neuroprotective effect. Nuclear factor erythroid 2-related factor (Nrf2)/BTB and CNC homology 1 (Bach1) ratio altering by Erk1/2 could ameliorate oxidative stress occurred in human macrophages. Primary cortical neuron cultures exposed to sevoflurane were assessed for cleaved caspase-1, cleaved caspase-3, Nrf2, Bach1, total Erk1/2, and phosphorylated Erk1/2 with the following: 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT); propidium iodide uptake (PI); lactate dehydrogenase (LDH); malondialdehyde (MDA); superoxide dismutase (SOD); Real-time PCR; and Western blot. We found that sevoflurane exposure increased cell pyroptosis, apoptosis, injury, and MDA (n=9, P<0.05), but decreased cell viability (n=9, P<0.05) and down-regulated SOD (n=9, P<0.05), while EPO partially rescued the neurotoxicity induced by sevoflurane (n=9, P<0.05), as well as increase the expression of Nrf2 mRNA and Nrf2/Bach1 ratio (n=9, P<0.05). Inhibition of Erk1/2 phosphorylation via PD98059 reversed the protective effect of EPO (n=9, P<0.05). Thus, protection of EPO markedly attenuated pyroptosis and apoptosis of neurons exposed to sevoflurane via Erk1/2-Nrf2/Bach1 signal pathway.
authors.affiliation: Department of Anesthesiology, Cangzhou Central Hospital, Cangzhou, China. Electronic address: azai2005@sina.com.
authors.forename: Rui
authors.initials: R
authors.lastname: Li
authors.affiliation: Department of Anesthesiology, Cangzhou Central Hospital, Cangzhou, China. Electronic address: azai2010@126.com.
authors.forename: Li-Min
authors.initials: LM
authors.lastname: Zhang
authors.affiliation: Department of Anesthesiology, Cangzhou Central Hospital, Cangzhou, China. Electronic address: 406403979@qq.com.
authors.forename: Wen-Bo
authors.initials: WB
authors.lastname: Sun
mesh_terms: D018685:Anesthetics, Inhalation / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis; D002470:Cell Survival / Q000187:drug effects; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism*; D004921:Erythropoietin / Q000008:administration & dosage / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D008738:Methyl Ethers / Q000494:pharmacology*; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D018696:Neuroprotective Agents / Q000008:administration & dosage; D018384:Oxidative Stress / Q000187:drug effects; D061251:Primary Cell Culture; D000069292:Pyroptosis; D017207:Rats, Sprague-Dawley; D000077149:Sevoflurane; D015398:Signal Transduction
chemical_list: D018685:Anesthetics, Inhalation; D008738:Methyl Ethers; D051267:NF-E2-Related Factor 2; D018696:Neuroprotective Agents; D004921:Erythropoietin; D000077149:Sevoflurane
keywords: Apoptosis; Erythropoietin; Neurotoxicity; Pyroptosis; Sevoflurane