The Protective Effect And Underlying Mechanisms Of Propofol Preconditioning In Post-cardiac Arrest Brain Injury

Backgroud:Cardiac arrest （CA） induced by asphyxia is a heavy accident in clinical anesthesia.Survivors after cardiopulmonary resuscitation often suffer from brain injury. However, CAinduced by asphyxia is still very difficult to cure due to the poor understanding of theunderlying mechanisms. Propofol has been widely used in intravenous anesthesia. Clinicaltrials and animal experiments indicated that propofol could exert significantneuroprotective effects following brain injury, but the underlying mechanism is not clearyet. Microglia are the primary resident immune cells in CNS. The activation of residentmicroglia depends on inflammatory events in brain injury. The results of study show thatmicroglial activation have a relationship between brain injury after cardiac arrest.Meantime the research in vitro indicated: propofol pre-conditioning inhibits microglial activation. In the present study, by using a rat model of asphyxia-induced cardiac arrest,combined methods including behavioral testing, molecular neurobiology, morphology andimmunohistochemistry, we elucidate the influence of microglial activation on CA-inducedbrain injury. Meanwhile, we sought to study propofol pre-conditioning effect of inhibitingbrain injury after asphyxia-induced cardiac arrest and microglial activation. Thus, ourstudy may provide further understanding on the neuroprotection of propofol and open newways for neuroprotective of perioperatie with cardiopulmonary resuscitation.Aims:To investigate the protective effects of propofol on CA-induced brain injury and itsunderlying mechanisms.Methods:（1） Establishment of a rat model of cardiac arrest induced by asphyxia andcardiopulmonary resuscitation（CPR）;（2） Immunoflurescent histochemistry was used todetect the microglial marker OX42in resuscitation rats;（3） Western blot analysis wasperformed to check the expression of Iba-1;（4） P2X₇R and p-p38were exclusivelyexpressed on the microglia by double immunoflurescent staining;（5） Western blot analysiswas used to check the expression of P2X₇R and p-p38;（6） Morris water maze wasperformed to test the spatial learning and memory after administering minocycline;（7）Western blot analysis was used to check the expression of Iba-1after administeringminocycline;（8） Western blot analysis was selected to check the expression of caspase-3after administering minocycline;（9） Morris water maze was performed to test the spatiallearning after propofol preconditioning;（10） Immunoflurescent histochemistry was usedto detect the P₂check the expression of P2X₇R and p-p38after propofolpreconditioning;（12） Western blot analysis was used to check the expression of caspase-3after propofol preconditioning;（13） Histological examination was performed to analysethe number of viable neurons after propofol preconditioning. Results:（1） Activated microglia with enhanced OX42-immunoreactivity was detected in theCA1region of the rat hippocampus;（2） Post-cardiac arrest brain injury increased Iba-1expression;（3） P2X₇R-immunoreactivity was exclusively co-localized with the microglialmarker OX42;（4） P-p38was also highly expressed on activated microglia;（5）Minocycline pre-treatment significantly prevented resuscitation-induced learning andmemory deficits;（6） Minocycline pre-treatment decreased expression of Iba-1;（7）Minocycline pre-treatment decreased expression of activated caspase-3level;（8） Propofolpre-conditioning significantly prevented resuscitation-induced learning and memorydeficits;（9） Propofol pre-conditioning significantly prevented resuscitation-inducedup-regulation of P2X₇R;（10） Propofol pre-conditioning significantly preventedresuscitation-induced up-regulation of p-p38;（11） Propofol pre-conditioning significantlydecreased activated caspase-3;（12） Propofol markedly attenuated the nissl-positive cellloss following resuscitation.Conclusions:（1）Post-cardiac arrest brain injury induces significant microglial activation in therat hippocampus.（2）Microglial activation is associated with up-regulation of p-p38and P2X₇R.（3）Resuscitation induces obvious learning and memory deficits, while minocyclinepre-treatment significantly prevent this outcome.（4）Propofol pre-conditioning inhibits resuscitation-induced microglial activationand neuronal injury in the hippocampus, which is probably related with the inhibitionof phosphorylated p38and P2X₇R.