Isoflurane Neurotoxicity Involves Activation Of Hypoxia Inducible Factor-1? Via Intracellular Calcium In Neonatal Rodents

Objective:Previousl,we found that the inhaled anesthetic isoflurane up-regulated the transcriptional factor hypoxia inducible factor?HIF?-1?protein levels during induction of neurodegeneration in the brain of neonatal rats.Here,we investigated the role of HIF-1?and the underlying signaling pathway in the neurodegenration induced by isoflurane in rodent developing brain.Methods:Primary hippocampal neurons were exposed to isoflurane?0.4 mM?for 12h.Neuron injury was analyzed by MTT test and quantification of lactate dehydrogenase release.HIF-1?gene expression and transcriptional activity,cleaved caspase-3 and phosphoinositide phospholipase C?PLC?-?gene expression were quantified.Cytosolic calcium concentration was measured by calcium imagine.The role of HIF-1?on juvenile learning and memory impairment induced by isoflurane was studied by fear conditioning and extinction test and Morris water maze test.Results:Isoflurane induced HIF-1?gene expression and transcriptional activity in vitro.Furthermore,pharmacological inhibition of HIF-1?or knockdown of HIF-1?by siRNA counteracted the neurotoxicity of isoflurane.Ca²⁺signaling pathways involving PLC-?activation are required for isoflurane-evoked HIF-1?accumulation.Finally,partial deficiency of HIF-1?attenuated isoflurane-induced neurodegeneration in developing brain,juvenile learning and memory impairment induced by isoflurane.Conclusions:HIF-1?activation via cytosolic Ca²⁺signaling pathway partially play a role in the mechanism of isoflurane-induced neurodegeneration in neonatal rodents,suggesting HIF-1?as potential therapeutic targets for the prevention of the deleterious effects of prolonged exposures to anesthetics.