Preconditioning with brief ischemia or spreading depression (SD) confers tolerance in cortical neurons to subsequent episode of ischemia. In myocardium a similar preconditioning is achieved by mechanisms, which are mediated by protein kinase C (PKC) alpha, delta, epsilon or zeta isoform. We induced SD by cortical application of KCl in the rat and analyzed cortical tissues after recovery of 30 min, 4 h and 12 h. While no changes at protein levels or activity of PKCalpha, epsilon or zeta were detected, a considerable increase in membrane translocation of PKCdelta was seen at 30 min and 12 h. A significant increase at mRNA level, protein amount and autophosphorylation at 12 h confirmed the late activation of PKCdelta, which may be involved in neuronal protection by preconditioning.