期刊
SCIENTIFIC REPORTS
卷 10, 期 1, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41598-020-58482-w
关键词
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资金
- Wellcome Trust [200633/z/16/z]
- Acorn fund, Keele University
- Wellcome Trust [200633/Z/16/Z] Funding Source: Wellcome Trust
This study compared effects of five hypoxia-inducible factor (HIF) prolyl hydroxylases (PHD) inhibitors on PC12 cells and primary rat neurons following oxygen-glucose deprivation (OGD). At 100 mu M, the PHD inhibitors did not cause cytotoxicity and apoptosis. MTT activity was only significantly reduced by FG4592 or Bayer 85-3934 in PC12 cells. The PHD inhibitors at 100 mu M significantly increased the LC3-II/LC3-I expression ratio and downregulated p62 in PC12 cells, so did FG4592 (30 mu M) and DMOG (100 mu M) in neurons. HIF-1 alpha was stabilised in PC12 cells by all the PHD inhibitors at 100 mu M except for DMOG, which stabilised HIF-1 alpha at 1 and 2 mM. In primary neurons, HIF-1 alpha was stabilised by FG4592 (30 mu M) and DMOG (100 mu M). Pretreatment with the PHD inhibitors 24 hours followed by 24 hour reoxygenation prior to 6 hours OGD (0.3% O-2) significantly reduced LDH release and increased MTT activity compared to vehicle (1% DMSO) pretreatment. In conclusion, the PHD inhibitors stabilise HIF-1 alpha in normoxia, induce autophagy, and protect cells from a subsequent OGD insult. The new class of PHD inhibitors (FG4592, FG2216, GSK1278863, Bay85-3934) have the higher potency than DMOG. The interplay between autophagy, HIF stabilisation and neuroprotection in ischaemic stroke merits further investigation.
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