Hypoxia causes transcriptional downregulation of protein kinase, anti-apoptotic and DNA repair genes in the hippocampal CA1 region; improved recovery from hypoxia with sevoflurane preconditioning correlates with preserved PKMζ gene expression

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Abstract Sevoflurane preconditioning improves recovery after hypoxia. Hypoxia interferes with protein expression at the translational level, however, its effect on DNA transcription of protein kinase and anti-apoptotic genes is unclear. Hippocampal slices were treated with 4% sevoflurane for 15 min, a 5 min washout, 10 min of hypoxia and 60 min of recovery. Quantitative real-time RT-PCR measured gene expression in the CA1 hippocampal region. The expression of protein kinases, PKCγ (0.22), PKCε (0.38), and PKMζ (0.55) mRNAs and anti-apoptotic, bcl-2 (0.44) and bcl-xl (0.41) mRNAs were reduced 60 min after hypoxia relative to their expression in tissue not subjected to hypoxia (set to1.0). Sevoflurane preconditioning prevented only the downregulation of PKMζ (0.88) mRNA after hypoxia. Pro-apoptotic BAD mRNA was not significantly changed after hypoxia even with sevoflurane preconditioning (0.81, 0.84 vs. 1.0); however, BAD mRNA was increased by sevoflurane in tissue not subjected to hypoxia (1.48). Poly ADP-ribose polymerase 1 (PARP-1), a DNA repair enzyme, was increased by sevoflurane in tissue not subjected to hypoxia (1.23). PARP-1 was reduced in untreated tissue after hypoxia (0.21); sevoflurane did not improve PARP-1 expression after hypoxia (0.27). In conclusion, hypoxia leads to a reduction of certain protein kinase, anti-apoptotic and DNA repair mRNAs, indicating that transcriptional downregulation may lead to neuronal damage. Sevoflurane prevents the downregulation of PKMζ mRNA which correlates with previous studies that found sevoflurane improved neuronal survival after hypoxia. Maintaining transcription of mRNA for critical proteins may provide an important mechanism for reducing neuronal damage after stroke.

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