Calpain inhibitors prevent nitric oxide-triggered excitotoxic apoptosis

The pathogenesis of some neurodegenerative disorders has been linked to exc itotoxicity, excess generation of nitric oxide (NO) and apoptosis. Here, we used a model of NO-triggered neuronal apoptosis that was strictly dependen t on autocrine NMDA receptor (NMDA-R) activation and intracellular Ca2+ inc rease. We investigated the efficiency and potentially beneficial effects of calpain inhibition. Three calpain inhibitors that prevented intracellular fodrin proteolysis also blocked apoptotic features such as decrease in mito chondrial membrane potential, chromatin breakdown, and subsequent death of cerebellar granule neurons exposed to NO donors (S-nitroso-L-glutathione, S -nitroso-N-acetyl-D,L-penicillamine, and diethy-lamino-diazenolate-2-oxide) . Since inhibitors did not interfere with NMDA-R activation, we suggest tha t block of calpains blunts NO-triggered neuronal apoptosis by stopping the cascade downstream of primary autocrine excitotoxic events. NeuroReport 12: 3645-3648 (C) 2001 Lippincott Williams & Wilkins.