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 voltage-gated Ca²⁺ 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 Zn²⁺ neurotoxicity. Administration of 3 to 10 mM aspirin, in cortical cell cultures, attenuated the evolution of neuronal death following exposure to 300 μM Zn²⁺ for 30 min. This neuroprotective effect of aspirin was attributable to the prevention of Zn²⁺ ion entry. Aspirin interfered with inward currents and an increase in [Ca²⁺]_i through VGCC and selective binding of ω-conotoxin, sensitive to N-type Ca²⁺ channel. The ω-conotoxins GVIA or MVIIC, the selective inhibitors of N-type Ca²⁺ channels, attenuated Zn²⁺ neurotoxicity. Aspirin derivatives lacking the carboxyl acid group did not reduce Zn²⁺ neurotoxicity. The present findings suggest that aspirin prevents Zn²⁺-mediated neuronal death by interfering with VGCC, and its action specifically requires the carboxyl acid group.