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- Title
Blockade of ionotropic glutamate receptors produces neuronal apoptosis through the Bax-cytochrome C-caspase pathway: the causative role of Ca[sup 2+] deficiency.
- Authors
Yoon, W. J.; Won, S. J.; Ryu, B. R.; Gwag, B. J.
- Abstract
Abstract Blockade of ionotropic glutamate receptors induces neuronal cell apoptosis. We investigated if mitochondria-mediated death signals would contribute to neuronal apoptosis following administration of glutamate antagonists. The administration of MK-801 and CNQX (MK-801/CNQX), the selective antagonists of N-methyl- d-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate receptors, produced widespread neuronal death in neonatal rat brain and cortical cell cultures. MK-801/CNQX-induced neuronal apoptosis was prevented by zVAD-fmk, a broad inhibitor of caspases, but insensitive to inhibitors of calpain or cathepsin D. Activation of caspase-3 was observed within 6–12 h and sustained over 36 h after exposure to MK-801/CNQX, which cleaved PHF-1 tau, the substrate for caspase-3. Activation of caspase-3 was blocked by high K[sup +] and mimicked by BAPTA-AM, a selective Ca[sup 2+] chelator. Reducing extracellular Ca[sup 2+], but not Na[sup +], activated caspase-3, suggesting an essential role of Ca[sup 2+] deficiency in MK-801/CNQX-induced activation of caspases. Cortical neurons treated with MK-801/CNQX triggered activation of caspase-9, release of cytochrome c from mitochondria, and translocation of Bax into mitochondria. The present study suggests that blockade of ionotropic glutamate receptors causes caspase-3-mediated neuronal apoptosis due to Ca[sup 2+] deficiency that is coupled to the sequential mitochondrial death pathway.
- Subjects
CHEMICAL inhibitors; NEURONS; APOPTOSIS; CYTOCHROMES; CALCIUM metabolism
- Publication
Journal of Neurochemistry, 2003, Vol 85, Issue 2, p525
- ISSN
0022-3042
- Publication type
Article
- DOI
10.1046/j.1471-4159.2003.01724.x