title: Isoflurane neurotoxicity involves activation of hypoxia inducible factor-1α via intracellular calcium in neonatal rodents.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors: Department of Anesthesiology and Pain Medicine, Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai 200001, China. Electronic address: 15130576782@163.com.
authors: Dongdong
authors: D
authors: Chai
authors: Department of Anesthesiology and Pain Medicine, Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai 200001, China. Electronic address: 1241921060@qq.com.
authors: Hong
authors: H
authors: Jiang
authors: Department of Anesthesiology and Pain Medicine, Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai 200001, China. Electronic address: liqifang2004@126.com.
authors: Qifang
authors: Q
authors: Li
mesh_terms: D018685:Anesthetics, Inhalation / Q000633:toxicity; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D006624:Hippocampus / Q000187:drug effects* / Q000254:growth & development* / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D007530:Isoflurane / Q000633:toxicity*; D007859:Learning Disabilities / Q000139:chemically induced / Q000378:metabolism; D008569:Memory Disorders / Q000139:chemically induced / Q000378:metabolism; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009410:Nerve Degeneration / Q000139:chemically induced / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D020258:Neurotoxicity Syndromes / Q000378:metabolism; D051966:Phospholipase C gamma / Q000378:metabolism; D017207:Rats, Sprague-Dawley
chemical_list: D018685:Anesthetics, Inhalation; C497443:Hif1a protein, mouse; C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007530:Isoflurane; D051966:Phospholipase C gamma; D002118:Calcium
keywords: Calcium; Hypoxia inducible factor-1α; Isoflurane; Neurotoxicity