Abstract
Mitochondria-dependent cell death is a primary mechanism of cell death in both acute and chronic neurodegenerative disorders, e.g., stroke and Alzheimer's disease. Ischemia, glutamate excitotoxicity and reactive oxygen species (ROS) all target the mitochondria. In response to these lethal stimuli, the mitochondria release death factors, primarily cytochrome c (Cyt c), initiating the apoptotic cascade. Cyt c release occurs by at least two mechanisms, i.e., mitochondrial permeability transition (mPT) and mitochondrial outer membrane permeabilization (MOMP) through a Bax channel. Blocking the release of Cyt c may have therapeutic potential in neurodegenerative disorders. Roche has described compounds that target the voltage-dependent anion channel component of the mPT. 2-Aminoethoxydiphenyl borate is able to inhibit Ca 2+ -induced Ca 2+ release, and tricyclic antidepressants can inhibit mPT. Substituted carbazoles from Serono are capable of blocking Bax channel formation and the release of Cyt c from isolated mitochondria. At MGI PHARMA, GPI-19410 was discovered to have a complex effect in blocking mitochondria-dependent cell death: it prevented mitochondrial depolarization in response to Ca 2+ , blocked Ca 2+ -induced mitochondrial swelling and Cyt c release, and blocked t-Bid-induced Cyt c release in a manner distinct from cyclosporin.
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