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

Authors
Kim, EY; Chang, SY; Chung, JM; Ryu, BR; Joo, CK; Moon, HS; Kang, K; Yoon, SH; Han, PL; Gwag, BJ
Citation
Neurobiology of disease, 8(5):774-783, 2001
Journal Title
Neurobiology of disease
ISSN
0969-99611095-953X
Abstract
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.
MeSH terms
Acetylcysteine/pharmacologyAnimalsAnti-Inflammatory Agents, Non-Steroidal/pharmacologyAntioxidants/pharmacologyApoptosis/drug effects*Aspirin/analogs & derivativesAspirin/chemistryAspirin/pharmacology*Benzoates/pharmacologyCalcium/metabolismCalcium Channels, N-Type/drug effectsCalcium Channels, N-Type/physiology*Cerebral Cortex/cytologyCerebral Cortex/drug effectsChromans/pharmacologyExcitatory Amino Acid Agonists/pharmacologyIon Channel Gating/drug effectsIon Transport/drug effects*Membrane Potentials/drug effectsMiceN-Methylaspartate/pharmacologyNerve Tissue Proteins/drug effectsNerve Tissue Proteins/physiology*Neurons/drug effects*Neurons/metabolismNeuroprotective Agents/pharmacology*Staurosporine/pharmacologyStructure-Activity RelationshipZinc/antagonists & inhibitorsZinc/pharmacologyZinc/toxicity*omega-Conotoxin GVIA/pharmacologyomega-Conotoxins/pharmacology
DOI
10.1006/nbdi.2001.0421
PMID
11592847
Appears in Collections:
Journal Papers > School of Medicine / Graduate School of Medicine > Pharmacology
AJOU Authors
유, 보름곽, 병주
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