Hypoxia inducible factor-1a is involved in the neurodegeneration induced by isoflurane in the brain of neonatal rats

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)-1a, a transcription factor, has been found regulating both prosurvival and prodeath pathways in the CNS. Previously, we found that isoflurane can activate HIF-1a under normoxic conditions in vitro and HIF-1a has been found to be involved in the pre-conditioning effect of isoflurane in various organs. Here, we investigated whether HIF-1a 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 S100 beta, cleaved caspase 3 and poly-(ADP-ribose) polymerase (PARP), respectively. Notably, isoflurane up-regulates HIF-1a 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-1a 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-1a is involved in the neurodegeneration induced by isoflurane in the brain of neonatal rats, suggesting HIF-1a may be a candidate for the dual effects of isoflurane on neuron fate.