Prevention of apoptotic neuronal death by controlling procaspases? A pointof view

In various animal models of neurodegenerative diseases the long-lasting con trol of cell death by anti-apoptotic therapies is not successful. We presen t here our view on the control of procaspase expression in a model of cereb ral stroke. We have investigated how Hu-Bcl-2 overexpression modifies cell death protein activation in a model of cerebral ischemia induced by permane nt middle cerebral artery occlusion (MCAO). In wild type mice MCAO induced release of cytochrome c from the mitochondria, and activation of caspases 9 and 3. In parallel with caspases activation, procaspase 9 and procaspase 3 were, respectively, increased and decreased. In Hu-Bcl-2 transgenic mice c ytochrome c release and caspases 9 and 3 activation were blocked. However p rocaspase 9 increased, like in wt mice, but procaspase 3 remained unchanged . By 2 weeks after MCAO caspases were no longer blocked in Hu-Bcl-2 transge nic mice. Procaspase 9 increase could represent a time bomb in Hu-Bcl-2 mic e where caspase 9 activation is blocked. Indeed, cellular accumulation of p rocaspase 9 is a potentially harmful event able to overcome anti-apoptotic protection by Bcl-2 and threaten cells with rapid destruction. Through unde rstanding of the upstream regulation of procaspase 9, early targets for the pharmacological control of apoptotic cell death may be revealed. (C) 2001 Elsevier Science B.V. All rights reserved.