Calpain inhibitors prevent nitric oxide-triggered excitotoxic apoptosis.
The pathogenesis of some neurodegenerative disorders has been linked to excitotoxicity, excess generation of nitric oxide (NO) and apoptosis. Here, we used a model of NO-triggered neuronal apoptosis that was strictly dependent on autocrine NMDA receptor (NMDA-R) activation and intracellular Ca2+ increase. 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 mitochondrial 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 diethylamino-diazenolate-2-oxide). Since inhibitors did not interfere with NMDA-R activation, we suggest that block of calpains blunts NO-triggered neuronal apoptosis by stopping the cascade downstream of primary autocrine excitotoxic events.
Volbracht
C
C
Molecular Toxicology, University of Konstanz, Konstanz, Germany.
Fava
E
E
Leist
M
M
Nicotera
P
P
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D019898:Autocrine Communication / Q000187:drug effects* / Q000502:physiology; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology; D002154:Calpain / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D002478:Cells, Cultured; D004249:DNA Damage / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D051379:Mice; D008815:Mice, Inbred Strains; D008840:Microfilament Proteins / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D019636:Neurodegenerative Diseases / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D009498:Neurotoxins / Q000494:pharmacology; D009569:Nitric Oxide / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000494:pharmacology; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects* / Q000378:metabolism; D013049:Spectrin
D002118:Calcium; D002154:Calpain; D002352:Carrier Proteins; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D008840:Microfilament Proteins; D009498:Neurotoxins; D009569:Nitric Oxide; D020030:Nitric Oxide Donors; D016194:Receptors, N-Methyl-D-Aspartate; D013049:Spectrin