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  • Title: Isoflurane neurotoxicity involves activation of hypoxia inducible factor-1α via intracellular calcium in neonatal rodents.
    Author: Chai D, Jiang H, Li Q.
    Journal: Brain Res; 2016 Dec 15; 1653():39-50. PubMed ID: 27769790.
    Abstract:
    OBJECTIVE: Previously, we found that the inhaled anesthetic isoflurane up-regulated the transcriptional factor hypoxia inducible factor (HIF)-1α protein levels during induction of neurodegeneration in the brain of neonatal rats. Here, we investigated the role of HIF-1α and the underlying signaling pathway in the neurodegenration induced by isoflurane in rodent developing brain. METHODS: Primary hippocampal neurons were exposed to isoflurane (0.4mM) for 12h. Neuron injury was analyzed by 3-(4,5-dimethyithiazol-2-yl)-2,5-diphenyl-tetra-zolium bromide (MTT) test and quantification of lactate dehydrogenaserelease. HIF-1α gene expression and transcriptional activity, cleaved caspase-3 and phosphoinositide phospholipase C (PLC)-γ gene expression were quantified. Cytosolic calcium concentration was measured by calcium imagining. The role of HIF-1α 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-1α gene expression and transcriptional activity in vitro. Furthermore, pharmacological inhibition of HIF-1α or knockdown of HIF-1α by shRNA counteracted the neurotoxicity of isoflurane. Ca2+ signaling pathways involving PLC-γ activation are required for isoflurane-evoked HIF-1α accumulation. Finally, partial deficiency of HIF-1α attenuated isoflurane-induced neurodegeneration in developing brain, and alleviated juvenile learning and memory impairment induced by isoflurane. CONCLUSION: HIF-1α activation via cytosolic Ca2+ signaling pathway play a role in the mechanism of isoflurane-induced neurodegeneration in neonatal rodents, suggesting HIF-1α as a potential therapeutic target for the prevention of the deleterious effects of prolonged exposures to anesthetics.
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