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 microM 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 omega-conotoxin, sensitive to N-type Ca2+ channel. The omega-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.
Kim
E Y
EY
Department of Pharmacology and Center for the Interventional Therapy of Stroke and Alzheimer's Disease, Ajou University School of Medicine, Suwon, Kyunggi-do, 442-749, Korea.
Chang
S Y
SY
Chung
J M
JM
Ryu
B R
BR
Joo
C K
CK
Moon
H S
HS
Kang
K
K
Yoon
S H
SH
Han
P L
PL
Gwag
B J
BJ
D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001241:Aspirin / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology*; D001565:Benzoates / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D020864:Calcium Channels, N-Type / Q000187:drug effects / Q000502:physiology*; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects; D002839:Chromans / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D015640:Ion Channel Gating / Q000187:drug effects; D017136:Ion Transport / Q000187:drug effects*; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D016202:N-Methylaspartate / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D019311:Staurosporine / Q000494:pharmacology; D013329:Structure-Activity Relationship; D015032:Zinc / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000633:toxicity*; D020866:omega-Conotoxin GVIA / Q000494:pharmacology; D020960:omega-Conotoxins / Q000494:pharmacology
C444539:2-acetoxymethylbenzoate; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000975:Antioxidants; D001565:Benzoates; D020864:Calcium Channels, N-Type; D002839:Chromans; D018690:Excitatory Amino Acid Agonists; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; C444540:ethyl-2-acetoxyethylbenzoate; D020960:omega-Conotoxins; C075851:omega-conotoxin-MVIIC; D016202:N-Methylaspartate; D020866:omega-Conotoxin GVIA; D019311:Staurosporine; D015032:Zinc; D001241:Aspirin; C010643:6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid; D002118:Calcium; D000111:Acetylcysteine