title: Caspase-dependent and -independent cell death induced by 3-nitropropionic acid in rat cortical neurons.
abstract: Mitochondria play a critical role in cell death by releasing apoptogenic factors, such as cytochrome c and apoptosis-inducing factor (AIF), from the intermembrane space into the cytoplasm. Because mitochondrial dysfunction has been shown to be involved in several neurodegenerative diseases, mitochondrial toxins are largely used to model these disorders. These include 3-nitropropionic acid (3-NP), an irreversible inhibitor of succinate dehydrogenase, which has been used to model Huntington's disease and was previously reported by us to induce apoptotic cell death through caspase activation. In the present study, we evaluated the involvement of caspase-independent neuronal cell death induced by 3-NP (1 mM) and the effect of z-VDVAD-fmk, an inhibitor of caspase-2, using cortical neurons in culture. Our results highly suggest that 3-NP induces both caspase-dependent and -independent cell death. We showed that z-VDVAD-fmk prevented both caspase-2 and -3-like activities evoked by 3-NP, but only partly prevented chromatin fragmentation/condensation. However, z-VDVAD-fmk did not avoid 3-NP-induced release of cytochrome c or AIF from mitochondria nor did it affect the levels of mitochondrial Bax. Furthermore, 3-NP-mediated decrease in plasma membrane integrity was not affected by z-VDVAD-fmk. Under these conditions, the inhibitor prevented the caspase-dependent cell death.
authors.affiliation: Institute of Biochemistry, Faculty of Medicine, University of Coimbra and Center for Neuroscience and Cell Biology of Coimbra, Coimbra, Portugal.
authors.forename: Sandra
authors.initials: S
authors.lastname: Almeida
authors.forename: Ana C
authors.initials: AC
authors.lastname: Brett
authors.forename: Inês N
authors.initials: IN
authors.lastname: Góis
authors.forename: Catarina R
authors.initials: CR
authors.lastname: Oliveira
authors.forename: A Cristina
authors.initials: AC
authors.lastname: Rego
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D020169:Caspases / Q000378:metabolism / Q000502:physiology*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects*; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology*; D009498:Neurotoxins / Q000494:pharmacology; D009574:Nitro Compounds / Q000494:pharmacology*; D011422:Propionates / Q000494:pharmacology*; D051381:Rats
chemical_list: D009498:Neurotoxins; D009574:Nitro Compounds; D011422:Propionates; D020169:Caspases; C015392:3-nitropropionic acid