Two caspase-mediated apoptotic pathways induced by rotenone toxicity in cortical neuronal cells.

Our results presented here suggest that cortical neurons degenerate via two caspase-mediated apoptotic pathways when challenged with 0.5 microM rotenone. Although these two pathways can be attributed to the loss of mitochondrial integrity, the triggers for these pathways are likely due to two separate subsequent events (the release of cytochrome c and the emergence of mitochondrial permeability transition [MPT]). Despite some reports suggesting that the release of cytochrome c is a consequence of MPT, the results of our time course experiments suggest otherwise. In fact, we observed that the release of cytochrome c occurred much earlier than MPT; hence, the former is unlikely to be a consequence of the latter. In addition, we observed that the presence of an MPT inhibitor did not attenuate the activation of caspase-3, and that caspase-1-mediated cell death did not exhibit nuclear condensation and DNA fragmentation. Taken together, these results suggest that there are two routes by which cortical neurons degenerate during ischemic injury or in neurodegenerative diseases.