title: The inhibition of lipoperoxidation by mesoionic compound MI-D: a relationship with its uncoupling effect and scavenging activity.
abstract: Important biological activities have been described for mesoionic compounds. We previously reported that MI-D (4-phenyl-5-(4-nitro-cinnamoyl)-1,3,4-thiadiazolium-2-phenylamine chloride) inhibited the respiratory chain, collapsed the transmembrane potential, and stimulated ATPase activity in intact rat liver mitochondria. It is known that drugs that affect mitochondrial membrane potential may facilitate the induction of cell death by apoptosis. Mitochondria have also a central role in the generation of reactive oxygen species, therefore it would be important to investigate how MI-D could affect processes related to oxidative stress. In this work, we evaluated the effects of MI-D on the lipoperoxidation and its ability to scavenge free radicals. Interestingly, it was observed that MI-D promoted a strong inhibition of the lipoperoxidation induced by Fe(3+)-ADP/2-oxoglutarate in isolated mitochondria (95%+/-0.27 at the highest concentration of 80 nmol mg(-1) protein) in a dose-dependent manner. However, at the same concentration its effect was less intense (22%+/-3.46) when the lipoperoxidation was initiated by peroxyl radicals generated from the azocompound AAPH. Lipid peroxidation in both coupled and uncoupled submitochondrial particles initiated with Fe(2+)/NADH was also inhibited by MI-D. The inhibition was about four times greater in coupled particles (approximately 34% at 80 nmol mg(-1) protein) in relation to uncoupled. MI-D inhibited the soybean phosphatidylcholine liposomes lipoperoxidation in a dose-dependent manner (5-80 microM) regardless of the radical being generated in lipid or aqueous phase. The mesoionic compound showed ability of scavenging superoxide radical (7, 11 and 31% for 25, 38 and 80 microM, respectively). Our results strongly suggest that the inhibition of lipoperoxidation promoted by MI-D is due to its scavenger action and to its previously described uncoupling effect.
authors.affiliation: Departamento de Bioquímica e Biologia Molecular, Universidade Federal do Paraná, C.P. 19046, CEP 81531-990, Curitiba, Paraná, Brazil.
authors.forename: Stelia Carolina
authors.initials: SC
authors.lastname: Mendez-Sanchez
authors.forename: Glaucia Regina
authors.initials: GR
authors.lastname: Martinez
authors.forename: Silvia
authors.initials: S
authors.lastname: Romão
authors.forename: Aurea
authors.initials: A
authors.lastname: Echevarria
authors.forename: Edson Fernandes
authors.initials: EF
authors.lastname: Silva
authors.forename: Maria Eliane Merlin
authors.initials: ME
authors.lastname: Rocha
authors.forename: Guilhermina Rodrigues
authors.initials: GR
authors.lastname: Noleto
authors.forename: Eva Gunilla Skare
authors.initials: EG
authors.lastname: Carnieri
authors.forename: Silvia Maria Suter Correia
authors.initials: SM
authors.lastname: Cadena
authors.forename: Maria Benigna Martinelli
authors.initials: MB
authors.lastname: de Oliveira
mesh_terms: D000578:Amidines / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002934:Cinnamates / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D016166:Free Radical Scavengers / Q000494:pharmacology*; D015227:Lipid Peroxidation / Q000187:drug effects*; D008081:Liposomes / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D010713:Phosphatidylcholines / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D013830:Thiadiazoles / Q000494:pharmacology*; D013997:Time Factors
chemical_list: C116348:4-phenyl-5-(4-nitrocinnamoyl)-1,3,4-thiadiazolium-2-phenylamine; D000578:Amidines; D002934:Cinnamates; D016166:Free Radical Scavengers; D008081:Liposomes; D010713:Phosphatidylcholines; D017382:Reactive Oxygen Species; D013830:Thiadiazoles; C046728:2,2'-azobis(2-amidinopropane)