Attenuation of Zn2+ neurotoxicity by aspirin: Role of N-type Ca2+ channel and the carboxyl acid group

Synaptically released Zn2+ ions enter into neurons primarily through voltag e-gated Ca2+ channels (VGCC) or N-methyl-D-aspartate (NMDA) receptors, whic h can mediate pathological neuronal death. We studied the possibility (and underlying mechanisms) that aspirin, known to prevent NMDA neurotoxicity, w ould also attenuate Zn2+ neurotoxicity. Administration of 3 to 10 mM aspiri n, in cortical cell cultures, attenuated the evolution of neuronal death fo llowing exposure to 300 muM Zn2+ for 30 min. This neuroprotective effect of aspirin was attributable to the prevention of Zn2+ ion entry. Aspirin inte rfered with inward currents and an increase in [Ca2+](i) through VGCC and s elective binding of omega -conotoxin, sensitive to N-type Ca2+ channel. The omega -conotoxins GVIA or MVIIC, the selective inhibitors of N-type Ca2+ c hannels, attenuated Zn-2+ neurotoxicity. Aspirin derivatives lacking the ca rboxyl acid group did not reduce Zn2+ neurotoxicity. The present findings s uggest that aspirin prevents Zn2+-mediated neuronal death by interfering wi th VGCC, and its action specifically requires the carboxyl acid group. (C) 2001 Academic Press.