title: Oxidative stress, mitochondrial permeability transition and activation of caspases in calcium ionophore A23187-induced death of cultured striatal neurons.
abstract: Disruption of intracellular calcium homeostasis is thought to play a role in neurodegenerative disorders such as Huntington's disease (HD). To study different aspects of putative pathogenic mechanisms in HD, we aimed to establish an in vitro model of calcium-induced toxicity in striatal neurons. The calcium ionophore A23187 induced a concentration- and time-dependent cell death in cultures of embryonic striatal neurons, causing both apoptosis and necrosis. Cell death was significantly reduced by the cell-permeant antioxidant manganese(III)tetrakis(4-benzoic acid) porphyrin (MnTBAP). Cyclosporin A and its analogue N-MeVal-4-cyclosporin also reduced the incidence of cell death, suggesting the participation of mitochondrial permeability transition in this process. Furthermore, addition of either of two types of caspase inhibitors, Ac-YVAD-CHO (acetyl-Tyr-Val-Ala-Asp-aldehyde) and Ac-DEVD-CHO (acetyl-Asp-Glu-Val-Asp-aldehyde), to the striatal cells blocked A23187-induced striatal cell death in a concentration-dependent manner. These results suggest that oxidative stress, opening of the mitochondrial permeability transition pore and activation of caspases are important steps in A23187-induced cell death.
authors.affiliation: Section for Neuronal Survival, Wallenberg Neuroscience Center, Department of Physiological Sciences, Sölvegatan 17, S-223 62, Lund, Sweden. asa.petersen@mphy.lu.se
authors.forename: A
authors.initials: A
authors.lastname: Petersén
authors.forename: R F
authors.initials: RF
authors.lastname: Castilho
authors.forename: O
authors.initials: O
authors.lastname: Hansson
authors.forename: T
authors.initials: T
authors.lastname: Wieloch
authors.forename: P
authors.initials: P
authors.lastname: Brundin
mesh_terms: D000818:Animals; D000001:Calcimycin / Q000633:toxicity*; D002118:Calcium / Q000378:metabolism*; D002128:Calcium Metabolism Disorders / Q000503:physiopathology; D020169:Caspases / Q000187:drug effects* / Q000378:metabolism*; D018929:Cell Culture Techniques; D016923:Cell Death / Q000187:drug effects* / Q000502:physiology*; D002463:Cell Membrane Permeability / Q000187:drug effects* / Q000502:physiology*; D003342:Corpus Striatum / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D016572:Cyclosporine / Q000494:pharmacology; D015853:Cysteine Proteinase Inhibitors; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016166:Free Radical Scavengers / Q000494:pharmacology; D007476:Ionophores / Q000633:toxicity*; D008665:Metalloporphyrins / Q000494:pharmacology; D008933:Mitochondrial Swelling / Q000187:drug effects* / Q000502:physiology*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism*; D009842:Oligopeptides / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
chemical_list: D015853:Cysteine Proteinase Inhibitors; D004791:Enzyme Inhibitors; D016166:Free Radical Scavengers; D007476:Ionophores; D008665:Metalloporphyrins; D009842:Oligopeptides; C099158:acetyl-aspartyl-glutamyl-valyl-aspartal; C097284:manganese(III)-tetrakis(4-benzoic acid)porphyrin; C096429:L 709049; D000001:Calcimycin; D016572:Cyclosporine; D020169:Caspases; D002118:Calcium