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Role of Caspases in N ‐Methyl‐ d ‐Aspartate‐Induced Apoptosis in Cerebrocortical Neurons
Author(s) -
Tenneti Lalitha,
D'Emilia Danielle M.,
Troy Carol M.,
Lipton Stuart A.
Publication year - 1998
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.1998.71030946.x
Subject(s) - caspase , microbiology and biotechnology , apoptosis , proteases , biology , intrinsic apoptosis , lipid peroxidation , mitochondrion , programmed cell death , nmda receptor , reactive oxygen species , chemistry , biochemistry , receptor , oxidative stress , enzyme
Overactivation of glutamate receptors mediates neuronal death in several acute and chronic neurodegenerative diseases. The intracellular processes underlying this form of death, however, remain poorly understood. Depending on the severity of insult, N ‐methyl‐ d ‐aspartate (NMDA) receptor activation induces either apoptosis or necrosis. Cysteine proteases related to interleukin‐1β‐converting enzyme (ICE), recently termed caspases, appear necessary for neuronal apoptosis in vivo and in vitro. To determine whether caspases play a role in NMDA‐induced apoptosis, we used two functionally distinct approaches to decrease substrate cleavage by caspases. One is a novel peptide (V‐ICE inh ) that contains the caspase catalytic site and acts as a pseudoenzyme that binds caspase substrates and prevents their cleavage. The other is a pseudosubstrate peptide (Z‐VAD·fmk) that inhibits caspase activity. Pretreatment with either V‐ICE inh or Z‐VAD·fmk protects cerebrocortical neurons from NMDA‐induced apoptosis, suggesting a role for caspases in NMDA‐induced apoptosis. To explore the signaling pathways involved, we looked at the effects of NMDA receptor activation on Ca 2+ influx, production of reactive oxygen species (ROS), mitochondrial membrane potential, and lipid peroxidation. Neither NMDA‐induced Ca 2+ influx nor the initial collapse of mitochondrial membrane potential could be prevented by pretreatment with V‐ICE inh or Z‐VAD·fmk. In contrast, ROS formation and lipid peroxidation were completely blocked by both V‐ICE inh and Z‐VAD·fmk. Taken together, our results suggest that Ca 2+ influx and mitochondrial depolarization occur upstream from caspase activation, whereas ROS formation and lipid peroxidation may be downstream events in the cascade leading to cortical neuronal apoptosis.