Mediation by membrane protein kinase C of zinc-induced oxidative neuronal injury in mouse cortical cultures.

Transsynaptic movement of endogenous zinc may play a key role in selective neuronal death after brain ischemia and prolonged seizures. As to the mechanism, we have reported recently that zinc-induced neuronal death occurs mainly by oxidative stress in cortical cultures. Here we present evidence supporting the idea that activation of membrane protein kinase C (PKC) in neurons is likely to play a key role in zinc-induced oxidative neuronal injury. Exposure of cortical cultures to 300 microM zinc for 15 min induced increases in the activity, without changing the amount, of membrane PKC to two- to threefold of control values, followed by neuronal death over the next day. Addition of a zinc chelator, Ca-EDTA, or PKC inhibitors with zinc completely abolished the zinc-induced increase in the membrane PKC activity. Indicating the participation of PKC in zinc-induced oxidative stress and neuronal death, the selective PKC inhibitor GF109203X attenuated both. Furthermore, as in zinc-induced neuronal death, activation of PKC with phorbol esters induced free radical generation and neuronal death, which were blocked by GF109203X or an antioxidant, Trolox. The present results support the idea that zinc influx activates PKC in the membrane, which contributes to free radical generation and neuronal death. As an increasing body of evidence suggests that zinc neurotoxicity is an important mechanism of pathological neuronal death, timely prevention of PKC activation after acute brain insult may prove useful in ameliorating this type of neuronal death.