Efeito neuroprotetor dos anestésicos intravenosos, Etomidato e Propofol, em um modelo de isquemia cerebral in vitro

Abstract

Several studies shows that propofol and etomidate, intravenous anesthetic, reduces neuronal injury due to brain ischemia. However, the results of such neuroprotection in ischemic models have been conflicting, both in vitro and in vivo studies. In addition, the mechanisms involved in propofol and etomidato neuroprotection have not been clarified. The aim of the present study was to investigate the neuroprotector effect of propofol and etomidate in a model of brain ischemia in vitro, as well as probable mechanisms involved. Methods: To investigate the neuroprotector effect of propofol and etomidate, we used the model hippocampus slices submitted to glucose and oxigen deprivation for 20 minutes. To investigate the possible sites of action of anesthetic neuroprotection, we evaluate the release of glutamate pathways involving calcium and sodium and oxidative stress. Results: In all the concentrations of propofol (1-300 M) and etomidate (1-100 M) evaluated were efficient in reducing neuronal death in the CA1 region of the hippocampus. Propofol and etomidate were able to reduce glutamate release after ischemic insult. This effect appears to be dependent on the reduction of propofol by the influx of Na+ by the Na+ channels voltage dependent tetrodotoxin-sensitive and the reduction on Ca2+ influx by the P/Q and N subtypes channels, from the extracellular environment. However etomidate reduces only Ca2+ influx by the P/Q and N subtypes channels, from the extracellular environment, acting on a greater extent than N channel P/Q. Etomidate has no effect on Na+ channels voltage dependent . In assay for quantifying ROS both, propofol and etomidato, in the concentration of 10 uM reduced ROS amount in relation to ischemia group. Lipid peroxidation assessment, propofol and etomidato, managed to reduce the MDA content to the level observed in the control group. In assessing the action of these anesthetics on the antioxidant defense system observed the following result: propofol and etomidate were able to increase the activity of the glutathione system enzymes, such as glutathione peroxidase and reductase, and increase the level of glutathione reduced available. Only propofol was able to positively modulate the activity of glutathione S-transferase. While only etomidate was able to increase the activity of superoxide dismutase and catalase, an effect not observed in the group treated with propofol. In addition, the antioxidant activity was observed per molecule of propofol itself. Conclusion: The intravenous anesthetic, propofol and etomidato, have neuroprotective effect in a model of hippocampal slices subjected to oxygen deprivation and low glucose, and this neuroprotective effect may be related to reduced glutamate release and attenuation of oxidative stress injury. The reduction in glutamate release in propofol group treated appears to occur due to the reduced influx of sodium by sodiumdependent voltage sensitive to tetrodotoxina channels and calcium P/Q and N subtype channels, from the extracellular medium. Already reduced glutamate release by etomidate seems to occur only due to reduced calcium influx of P/Q and N subtype channels, from the extracellular medium. The attenuation of oxidative stress injury is directly related to the ability of these anesthetics reduce the amount of reactive oxygen species and lipid peroxidation after the ischemic insult. This fact is explained by the positive modulation of the activity of the enzymes of the antioxidant system and the antioxidant activity of propofol itself.