title: Hypoxia inducible factor-1α is involved in the neurodegeneration induced by isoflurane in the brain of neonatal rats.
abstract: More and more data show isoflurane, a commonly used volatile anesthetic has dual effects on neuron fate. However, the underlying mechanisms that can explain the apparent paradox are poorly understood. Hypoxia inducible factor (HIF)-1α, a transcription factor, has been found regulating both prosurvival and prodeath pathways in the CNS. Previously, we found that isoflurane can activate HIF-1α under normoxic conditions in vitro and HIF-1α has been found to be involved in the pre-conditioning effect of isoflurane in various organs. Here, we investigated whether HIF-1α is a contributing factor in the neurodegenration in rodent primary cultured neurons and in developing rat brain. Isoflurane dose-dependently induced apoptotic neurodegeneration in neonatal rats as assessed by S100β, cleaved caspase 3 and poly-(ADP-ribose) polymerase (PARP), respectively. Notably, isoflurane up-regulates HIF-1α protein levels in vivo and in vitro during induction of neurodegeneration. Likewise, isoflurane resulted in a significant elevation of cytosonic calcium levels in neuron cultures. Furthermore, knockdown of HIF-1α expression in cultured neurons attenuated isoflurane-induced neurotoxicity. Finally, Morris water maze (MWM) test showed neonatal exposure to isoflurane impaired juvenile learning and memory ability in rats. These findings indicate that HIF-1α is involved in the neurodegeneration induced by isoflurane in the brain of neonatal rats, suggesting HIF-1α may be a candidate for the dual effects of isoflurane on neuron fate.
authors.affiliation: Department of Anesthesiology, Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Jiang
authors.forename: Yan
authors.initials: Y
authors.lastname: Huang
authors.forename: Hui
authors.initials: H
authors.lastname: Xu
authors.forename: Yu
authors.initials: Y
authors.lastname: Sun
authors.forename: Ning
authors.initials: N
authors.lastname: Han
authors.forename: Qi Fang
authors.initials: QF
authors.lastname: Li
mesh_terms: D018685:Anesthetics, Inhalation / Q000633:toxicity*; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D007530:Isoflurane / Q000633:toxicity*; D007859:Learning Disabilities / Q000139:chemically induced; D008569:Memory Disorders / Q000139:chemically induced; D009414:Nerve Growth Factors / Q000097:blood; D019636:Neurodegenerative Diseases / Q000139:chemically induced* / Q000150:complications / Q000473:pathology*; D009474:Neurons / Q000187:drug effects; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins / Q000097:blood; D014162:Transfection; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D018685:Anesthetics, Inhalation; C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009414:Nerve Growth Factors; D034741:RNA, Small Interfering; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins; D007530:Isoflurane; D002118:Calcium