Aspirin prevention of NMDA-induced neuronal death by direct protein kinase Czeta inhibition.
Abstract Aspirin has been shown to protect against glutamate neurotoxicity via the nuclear factor kappaB 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 PKCzeta, decreasing the NMDA-induced activation, cleavage and nuclear translocation of this molecule. Aspirin (acetylsalicylic acid) directly inhibited the protein kinase activity of PKCzeta, whereas salicylic acid did not. This direct effect of aspirin on purified human PKCzeta is consistent with PKCzeta inhibition preventing the NMDA-induced death of cortical neurones. Caspase-3 inhibition blocked the cleavage and nuclear translocation of PKCzeta, whereas caspase-1-inhibition did not. Thus, PKCzeta (protein kinase Mzeta) 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 PKCzeta, a key molecule in inflammatory responses and neurodegeneration.
Crisanti
P
P
Unité 598 de l'Institut National de la Sante Et de la Recherche Medicale: Physiopathologie des maladies oculaires: Innovations thérapeutiques, Paris, France.
Leon
A
A
Lim
D M
DM
Omri
B
B
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001241:Aspirin / Q000494:pharmacology*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002467:Cell Nucleus / Q000187:drug effects / Q000201:enzymology; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity; D016202:N-Methylaspartate / Q000633:toxicity*; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D018696:Neuroprotective Agents / Q000494:pharmacology; D016716:PC12 Cells; D011493:Protein Kinase C / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D000099221:Protein Kinase C zeta
D000894:Anti-Inflammatory Agents, Non-Steroidal; D001241:Aspirin; D053148:Caspase 3; D020169:Caspases; D018690:Excitatory Amino Acid Agonists; D016202:N-Methylaspartate; D018696:Neuroprotective Agents; D011493:Protein Kinase C; D000099221:Protein Kinase C zeta; C505407:CASP3 protein, human; C505410:Casp3 protein, rat