An active, cytochrome c-dependent mitochondrial death pathway contributes to excitotoxic neuronal necrosis, challenging the traditional view that it is purely a passive mechanism.
Challenges passive view of excitotoxic necrosis; hypothesis-generating for caspase pathways, clinical translation undetermined.
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.
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Seo et al. (2009) studied Excitotoxic neuronal necrosis. Caspase inhibitors (z-LEHD-fmk, z-DEVD-fmk, or Q-VD-oph) vs. Glutamate + vehicle was evaluated on Percentage of propidium iodide-positive neurons.
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