Stroke is the second leading cause of death in the world. Unfortunately, only a few drugs have been proved in clinical trials. Drug development of the last decade has been focused substantially on a promising and heterogeneous group of neuroprotective drugs. Hundreds of compounds were suggested as new putative neuroprotectors, which effectiveness was confirmed in preclinical trials only. At the present time discrepancy between results of preclinical studies and clinical trials requires careful analysis. One of the least evaluated and probably the most noticeable reasons is general anesthesia--an obligatory component of an overwhelming majority of existing animal stroke models. The aim of the review is to describe known mechanisms of common general anesthetics influence on ionotropic and metabotropic plasma membrane receptors, and key signal pathways involved in neuronal hypoxic-ischemic injury and survival.
Uspekh éksperimental'nykh i proval klinicheskikh issledovaniĭ neĭroprotektornykh preparatov v terapii ishemicheskogo insul'ta opredeliaet neobkhodimost' analiza sushchestvuiushchikh modeleĭ. Protokol bol'shinstva laboratornykh modeleĭ insul'ta vkliuchaet obshchuiu anesteziiu. Ingaliatsionnye i vnutrivennye anestetiki vliiaiut na signal'nye puti, uchastvuiushchie v neĭroprotektornykh i neĭrotoksicheskikh mekhanizmakh. Aktivatsiia ionotropnykh glutamatergicheskikh AMPA- i NMDA-retseptorov v ishemizirovannoĭ tkani golovnogo mozga soprovozhdaetsia nekrozom i apoptozom neĭronov. Otdel'nye anestetiki izmeniaiut aktivnost' AMPA-retseptorov, v tom chisle putem fosforilirovaniia i internalizatsiii/éksternalizatsii GluR-sub"edinits retseptora. Riad anestetikov pomimo priamoĭ blokady NMDA-retseptorov vliiaet na protsessy fosforilirovaniia i ékspressii NR1-sub"edinitsy NMDA-retseptora. Mekhanizm deĭstviia mnogikh ingaliatsionnykh i vnutrivennykh anestetikov sviazan s aktivatsieĭ ionotropnykh GAMKA-retseptorov, chto povyshaet rezistentnost' kletok k éksaĭtotoksichnosti i snizhaet ishemicheskoe povrezhdenie neĭronov. Nariadu s ionotropnymi retseptorami mishen'iu riada anestetikov iavliaiutsia metabotropnye transmembrannye retseptory, sopriazhennye s G-belkami. Anestetiki oposredovanno vliiaiut na metabotropnye GAMKB- i glutamatnye mGlu-retseptory putem reguliatsii belok-belkovykh vzaimodeĭstviĭ i fosforilirovaniia sub"edinits retseptorov. Nekotorye ingaliatsionnye i vnutrivennye anestetiki aktiviruiut adenozinovye A1-retseptory, povyshaia kontsentratsiiu adenozina vne kletki. Prekonditsionirovanie anestetikami mozhet soprovozhdat'sia dlitel'noĭ neĭroprotektsieĭ, sopriazhennoĭ s aktivatsieĭ p38 MAPK i transkriptsionnykh faktorov mTOR i CREB. Vozmozhnym resheniem problemy vliianiia anestetikov na rezul'taty laboratornykh issledovaniĭ iavliaetsia primenenie v parallel'nykh gruppakh sravneniia razlichnykh sredstv obshcheĭ anestezii. Éffekty obshchikh anestetikov opredeliaiut neobkhodimost' izucheniia ikh neĭroprotektornogo potentsiala v usloviiakh ishemicheskogo insul'ta.
Keywords: general anesthetics; neuroprotection; signal pathways; stroke models.