title: Inhibition of MG132-induced mitochondrial dysfunction and cell death in PC12 cells by 3-morpholinosydnonimine.
abstract: The effect of 3-morpholinosydnonimine (SIN-1) against the cytotoxicity of MG132, a proteasome inhibitor, in differentiated PC12 cells was assessed by measuring the effect on the mitochondrial membrane permeability. Treatment of PC12 cells with MG132 resulted in the nuclear damage, decrease in the mitochondrial transmembrane potential, cytosolic accumulation of cytochrome c, activation of caspase-3, increase in the formation of reactive oxygen species (ROS), and depletion of GSH. Addition of SIN-1, a producer of nitric oxide (NO) and superoxide, differentially reduced the MG132-induced cell death and GSH depletion concentration dependently with a maximal inhibitory effect at 150 microM. Carboxy-PTIO, superoxide dismutase, Mn-TBAP, and ascorbate prevented the inhibitory effect of SIN-1 on the cytotoxicity of MG132. SIN-1 inhibited the MG132-induced change in the mitochondrial membrane permeability, ROS formation and decrease in GSH contents in PC12 cells. S-nitroso-N-acetyl-DL-penicillamine reduced the MG132-induced cell death in PC12 cells, whereas peroxynitrite and H2O2 did not affect the cytotoxicity of MG132. The results suggest that NO and superoxide liberated from SIN-1 exert an inhibitory effect against the cytotoxicity of MG132. SIN-1 may inhibit the MG132-induced viability loss in PC12 cells by suppressing change in the mitochondrial membrane permeability that is associated with oxidative damage.
authors.affiliation: Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul 156-756, South Korea. leecs@cau.ac.kr
authors.forename: Chung Soo
authors.initials: CS
authors.lastname: Lee
authors.forename: Eun Sook
authors.initials: ES
authors.lastname: Han
authors.forename: Eon Sob
authors.initials: ES
authors.lastname: Park
authors.forename: Hyoweon
authors.initials: H
authors.lastname: Bang
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002463:Cell Membrane Permeability / Q000187:drug effects / Q000502:physiology; D015853:Cysteine Proteinase Inhibitors / Q000633:toxicity; D045304:Cytochromes c / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004734:Energy Metabolism / Q000187:drug effects / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005609:Free Radicals / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D007976:Leupeptins / Q000037:antagonists & inhibitors* / Q000633:toxicity; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D008981:Molsidomine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D009569:Nitric Oxide / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D016716:PC12 Cells; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D051381:Rats; D013481:Superoxides / Q000378:metabolism
chemical_list: D000975:Antioxidants; D015853:Cysteine Proteinase Inhibitors; D004791:Enzyme Inhibitors; D005609:Free Radicals; D007976:Leupeptins; D020030:Nitric Oxide Donors; D061988:Proteasome Inhibitors; D013481:Superoxides; D009569:Nitric Oxide; C002385:linsidomine; D045304:Cytochromes c; D008981:Molsidomine; D046988:Proteasome Endopeptidase Complex; D005978:Glutathione; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde