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1,2-bis(2-Aminophenoxy)ethane-N,N,N',N'-tetraacetic acid induces caspase-mediated apoptosis and reactive oxygen species-mediated necrosis in cultured cortical neurons.

Han, KS; Kang, HJ; Kim, EY; Yoon, WJ; Sohn, S; Kwon, HJ; Gwag, BJ
Journal of neurochemistry, 78(2):230-239, 2001
Journal Title
Journal of neurochemistry
Sustained alteration in [Ca(2+)]i triggers neuronal death. We examined morphological and signaling events of Ca(2+)-deficiency-induced neuronal death. Cortical cell cultures exposed to 20 microM 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA-AM), an intracellular calcium chelator, underwent neuronal apoptosis within 12 h that was evident by shriveled cell bodies, aggregated and condensed nuclear chromatin, and disrupted nuclear membrane. Thereafter, surviving neurons revealed typical necrosis, accompanied by swelling of cell body and mitochondria, over 24 h. Both apoptosis and necrosis were prevented by inclusion of 1 microg/mL cycloheximide, a protein synthesis inhibitor. Treatment with BAPTA-AM induced translocation of Bax into mitochondria within 4 h and release of cytochrome c from mitochondria over 4-12 h. An active fragment of caspase-3, a downstream mediator of cytochrome c, was observed within 8 h and cleaved PHF-1-positive tau. Administration of zVAD-fmk, a broad inhibitor of caspases, or DEVD-amc, a selective inhibitor of caspase-3, selectively prevented the apoptosis component of BAPTA-AM neurotoxicity. In contrast, BAPTA-AM-induced necrosis was propagated through sequential production of superoxide, mitochondrial and cytoplasmic reactive oxygen species. Combined treatment with caspase inhibitors and antioxidants blocked BAPTA-AM neurotoxicity. The present study suggests that neurons deficient in [Ca(2+)]i undergo caspase-3-mediated apoptosis and reactive oxygen species (ROS)-mediated necrosis.
MeSH terms
6-Cyano-7-nitroquinoxaline-2,3-dione/pharmacologyAnimalsAnimals, NewbornApoptosis/drug effectsApoptosis/physiology*Caspases/metabolism*Cell Death/drug effectsCells, CulturedCerebral Cortex/cytology*Cerebral Cortex/physiologyChelating Agents/pharmacologyChromans/pharmacologyCycloheximide/pharmacologyCysteine Proteinase Inhibitors/pharmacologyDizocilpine Maleate/pharmacologyEgtazic Acid/analogs & derivativesEgtazic Acid/pharmacology*FetusKineticsMiceMice, Inbred ICRNecrosisNeocortex/cytologyNeocortex/physiologyNeuroglia/cytology*Neuroglia/drug effectsNeuroglia/physiologyNeurons/cytology*Neurons/physiology*Neurons/ultrastructureNeuroprotective Agents/pharmacologyReactive Oxygen Species/physiology*Time Factors
Appears in Collections:
Journal Papers > School of Medicine / Graduate School of Medicine > Microbiology
Journal Papers > School of Medicine / Graduate School of Medicine > Pharmacology
AJOU Authors
손, 성향곽, 병주
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