Abstract
The neuroprotective role of propofol in transient global and focal cerebral ischemia reperfusion (I/R) animal model has recently been highlighted. However, no studies have conducted to explore the relationship between mitochondrial fission/fusion and I/R injury under the intervention of propofol. Moreover, neuroprotective mechanism of propofol is yet unclear. Culturing primary hippocampal cells were subjected to oxygen-glucose deprivation and re-oxygenation (OGD/R) model, as a model of cerebral I/R in vitro. Methods CCK-8 assay was used to test the effect of propofol on cell viability. We examined the effect of propofol on mitochondrial ultrastructure and mitochondrial fission evoked by OGD/R with transmission electron microscopy and immunofluorescence assay. To investigate possible neuroprotective mechanisms, the authors then examined whether propofol could inhibit calcium-overload, calcineurin (CaN) activation and the phosphorylation of dynamin-related protein 1 (Drp1) during the period of OGD/R, as well as the combination of Drp1-ser 637 and fission 1 (Fis1) protein by immunofluorescence assay, ELISA and double-labeling immunofluorescence analysis. Finally, the expression of Drp1-ser 637 and Fis1, apoptosis inducing factor (AIF) and cytochrome C (Cyt C) were detected by western blot. When added in culture media during OGD period, propofol (0.1μM-50μM) could alleviate neurons injury and protect mitochondrial ultrastructure, meanwhile inhibit mitochondrial fission. Furthermore, the concentration of intracellular free Ca2+, CaN activition and the phosphorylation of Drp1-ser637 were suppressed, as well as the translocation and combination of Drp1-ser 637 and Fis1. The authors also found that the expression of Cyt C, AIF, Drp1-ser637 and Fis1 were down-regulated. Notably, high dose of propofol (100μM-200μM) were confirmed to decrease the survival of neurons based on results of cell viability. Propofol could inhibit mitochondrial fission and mitochondrial apoptotic pathway evoked by OGD/R in rat hippocampal neurons, which may be via depressing calcium-overload.
Highlights
Ischemic brain injury, a serious occurring complication of shock, cardiac arrest, cardiopulmonary bypass or accidents during operation and anesthesia, is a main cause of death and disability in adults[1]
There was no research designed to explore whether propofol could protect neurons from ischemia reperfusion (I/R) injury through acting on the dynamic balance between mitochondrial fission and fusion, which had been proven to play a vital role on apoptosis during I/R injury[29]
We revealed that the probable mechanism may be that propofol inhibited mitochondrial fission by the phosphorylation of dynamin-related protein 1 (Drp1)-Ser637 and its translocation to mitochondrion, which caused by CaN, activated by intracellular Ca2+ (Figs 2–4)
Summary
A serious occurring complication of shock, cardiac arrest, cardiopulmonary bypass or accidents during operation and anesthesia, is a main cause of death and disability in adults[1]. The key treatment of ischemic injury is to reestablish blood supply for ischemic region in its narrow therapeutic time windows. The doctor would not accept these therapies because of the further injury followed by reperfusion[2]. Recent studies have suggested that anesthetic drugs have neuroprotective effects on cerebral I/R injury via reducing cerebral blood flow(CBF) and cerebral metabolic rate of oxygen(CMRO)[3,4], and extensive experimental confirmed it. It has been confirmed that propofol reduced ischemic brain injury via gultamatergic signaling pathway in rats [8]
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