PROPOFOL PREVENTS CEREBRAL ISCHEMIA-TRIGGERED AUTOPHAGY ACTIVATION AND CELL DEATH IN THE RAT HIPPOCAMPUS THROUGH THE NF-KB/P53 SIGNALING PATHWAY

摘要

Propofol (2,6-diisopropylphenol) has been shown to attenuate neuronal injury under a number of experimental conditions; however, the mechanisms involved in its neuro-protective effects remain unclear. We therefore investigated whether inhibition of p53 induction by propofol contributes to the neuroprotection of cerebral ischemic cell death through both autophagic and apoptotic mechanisms. A transient global cerebral ischemia-reperfusion (I/R) model was produced with a 10-min, 2-vessel occlusion. The change in target genes including damage-regulated autophagy modulator (DRAM), microtubule-associated protein 1 light chain 3 (LC3), Beclin 1, cathepsin D, cathepsin B, p53-upregulated modulator of apoptosis (PUMA), Bax and Bcl-2 upon p53 inhibition was assessed with the co-administration of the intravenous anesthetic propofol and 3-methyladenine (3-MA), Pifithrin-alpha (PFT-alpha) or SN50. The l/R-induced increases of protein levels of p53 and LC3-II were significantly inhibited by treatment with propofol, 3-MA or PFT-alpha. The l/R-induced increases of protein levels of DRAM, Beclin 1, active cathepsin D and cathepsin B were significantly inhibited by treatment with propofol, PFT-alpha or SN50. The negative effects of the l/R-induced up-regulation of PUMA and Bax and the down-regulation of Bcl-2 in the rat hippocampus were all blocked by treatment with propofol, PFT-alpha or SN50. Our results suggest that cerebral I/R can induce nuclear factor-kappa B-dependent expression of p53. The autophagic and apoptotic mechanisms participate in programed cell death by regulating the p53-mediated pathway. Our results are the first to show that propofol, at clinically relevant concentrations, attenuated cell death through both autophagic and apoptotic mechanisms in the rat hippocampus after a cerebral I/R insult.