Cortexin, a drug containing hydrolyzed brain peptides, has long been used in clinics, but the mechanisms of its action remain obscure. We have hypothesized that cortexin-related neuroprotection is associated with the ability of the drug to inhibit brain proteases. Cortexin effectively inhibited brain caspase-8, while its effects on caspase-1, -3, -9, cathepsin B and calpain were much less pronounced or absent. In addition, we isolated a peptide fraction from cortexin holding all the inhibitory capacity of the original drug, but with a much more simple composition. Both cortexin and its fraction prevented neuronal damage in a culture model of glutamate-induced cell death. Neuroprotective effect of Cortexin may be mediated by inhibition of the initiator caspase-8 in the brain.
Peptidnyĭ preparat korteksin davno ispol'zuetsia v klinike, odnako mekhanizmy deĭstviia étogo preparata ostaiutsia nedostatochno issledovannymi. Éto delaet aktual'nym izuchenie molekuliarnykh mekhanizmov vliianiia korteksina na funktsionirovanie mozga i, prezhde vsego, poisk pervichnykh molekuliarnykh misheneĭ. My predpolozhili, chto neĭroprotektornoe deĭstvie korteksina sviazano s ego sposobnost'iu ingibirovat' proteazy, prinimaiushchie uchastie v gibeli kletok mozga. V rezul'tate provedennykh éksperimentov ustanovleno, chto korteksin sposoben éffektivno ingibirovat' kaspazu-8 mozga. Krome kaspazy-8 byli issledovany drugie proteazy, kaspazy-1, -3 i -9, katepsin V i kal'pain, no oni ingibiruiutsia korteksinom menee éffektivno, libo ne ingibiruiutsia sovsem. Iz korteksina byla vydelena fraktsiia vodorastvorimykh peptidov, obladaiushchaia vsemi ingibiruiushchimi proteazy svoĭstvami iskhodnogo korteksina, no znachitel'no bolee prostaia po sostavu. Kak korteksin, tak i vydelennaia iz nego peptidnaia fraktsiia sposobny v éksperimentakh in vitro predotvrashchat' indutsirovannuiu glutamatom gibel' neĭronov. Takim obrazom, neĭroprotektornoe deĭstvie korteksina mozhet byt' oposredovano priamym ingibirovaniem initsiatornoĭ kaspazy-8 mozga.
Keywords: brain; caspases; cortexin; peptides; proteases.