The peptide-based drug cortexin inhibits brain caspase-8

Abstract

Although the peptide-based drug cortexin is used in clinical practice for a long time, the mechanisms of its action still remain poorly investigated. This underlies importance of elucidation of the molecular mechanisms responsible for the cortexin impact on brain functioning and identification of primary molecular targets. We hypothesized that the neuroprotective effects of cortexin may be associated with its ability to inhibit brain proteases involved in death of brain cells. Results of this study have shown that cortexin can effectively inhibit brain caspase-8. Other investigated proteases (caspase-1, -3, -9, cathepsin B, and calpain) demonstrated either lower sensitivity or lack of sensitivity to inhibition by cortexin. The original protease inhibitory activity of cortexin was also detected in a (more simple in composition) water-soluble fraction of peptides isolated from cortexin. Both cortexin and the isolated peptide fraction prevented glutamate-induced neuronal death in vitro. Thus the neuroprotective effect of cortexin may be associated with direct inhibition of the brain initiator caspase-8.