Attenuation of Zn 2+ neurotoxicity by aspirin: Role of N-type Ca 2+ channel and the carboxyl acid group

Abstract

Synaptically released Zn 2+ ions enter into neurons primarily through voltage-gated Ca 2+ channels (VGCC) or N-methyl-D-aspartate (NMDA) receptors, which can mediate pathological neuronal death. We studied the possibility (and underlying mechanisms) that aspirin, known to prevent NMDA neurotoxicity, would also attenuate Zn 2+ neurotoxicity. Administration of 3 to 10 mM aspirin, in cortical cell cultures, attenuated the evolution of neuronal death following exposure to 300 μM Zn 2+ for 30 min. This neuroprotective effect of aspirin was attributable to the prevention of Zn 2+ ion entry. Aspirin interfered with inward currents and an increase in [Ca 2+] i through VGCC and selective binding of ω-conotoxin, sensitive to N-type Ca 2+ channel. The ω-conotoxins GVIA or MVIIC, the selective inhibitors of N-type Ca 2+ channels, attenuated Zn 2+ neurotoxicity. Aspirin derivatives lacking the carboxyl acid group did not reduce Zn 2+ neurotoxicity. The present findings suggest that aspirin prevents Zn 2+-mediated neuronal death by interfering with VGCC, and its action specifically requires the carboxyl acid group. © 2001 Academic Press.