Aspirin prevention of NMDA-induced neuronal death by direct protein kinase Cζ inhibition

Aspirin has been shown to protect against glutamate neurotoxicity via the nuclear factor kappa B pathway. Some studies have implicated the atypical protein kinase C (PKC) zeta (zeta) isoform in cell protection, but the mechanism involved remains unclear. We show here that aspirin exerts at least some of its effects through PKC zeta, decreasing the NMDA-induced activation, cleavage and nuclear translocation of this molecule. Aspirin (acetylsalicylic acid) directly inhibited the protein kinase activity of PKC zeta, whereas salicylic acid did not. This direct effect of aspirin on purified human PKC zeta is consistent with PKC zeta inhibition preventing the NMDA-induced death of cortical neurones. Caspase-3 inhibition blocked the cleavage and nuclear translocation of PKC zeta, whereas caspase-1-inhibition did not. Thus, PKC zeta (protein kinase M zeta) regulates nuclear events essential for the initiation of the apoptotic pathway. Aspirin protects cells against NMDA-induced apoptosis by means of a novel mechanism targeting PKC zeta, a key molecule in inflammatory responses and neurodegeneration.