Contribution of a mitochondrial pathway to excitotoxic neuronal necrosis

✍ Scribed by Dae-Won Seo; Maria-Leonor Lopez-Meraz; Suni Allen; Claude Guy Wasterlain; Jerome Niquet

• Publisher: John Wiley and Sons
• Year: 2009
• Tongue: English
• Weight: 919 KB
• Volume: 87
• Category: Article
• ISSN: 0360-4012
• DOI: 10.1002/jnr.22035

✦ Synopsis

Abstract

It is traditionally thought that excitotoxic necrosis is a passive mechanism that does not require the activation of a cell death program. In this study, we examined the contribution of the cytochrome c‐dependent mitochondrial death pathway to excitotoxic neuronal necrosis, induced by exposing cultured cortical neurons to 1 mM glutamate for 6 hr and blocked by the NMDA antagonist, dizocilpine. Glutamate treatment induced early cytochrome c release, followed by activation of caspase‐9 and caspase‐3. Preincubation with the caspase‐9 inhibitor z‐LEHD‐fmk, the caspase‐3 inhibitor z‐DEVD‐fmk, or the specific pan‐caspase inhibitor Q‐VD‐oph decreased the percentage of propidium iodide‐positive neurons (52.5% ± 3.1%, 39.4% ± 3.5%, 44.6% ± 3%, respectively, vs. 65% ± 3% in glutamate + vehicle). EM studies showed mitochondrial release of cytochrome c in neurons in the early stages of necrosis and cleaved caspase‐3 immunoreactivity in morphologically necrotic neurons. These results suggest that an active mechanism contributes to the demise of a subpopulation of excitotoxic necrotic neurons. © 2009 Wiley‐Liss, Inc.