title: Pristanic acid provokes lipid, protein, and DNA oxidative damage and reduces the antioxidant defenses in cerebellum of young rats.
abstract: Zellweger syndrome (ZS) and some peroxisomal diseases are severe inherited disorders mainly characterized by neurological symptoms and cerebellum abnormalities, whose pathogenesis is poorly understood. Biochemically, these diseases are mainly characterized by accumulation of pristanic acid (Prist) and other fatty acids in the brain and other tissues. In this work, we evaluated the in vitro influence of Prist on redox homeostasis by measuring lipid, protein, and DNA damage, as well as the antioxidant defenses and the activities of aconitase and α-ketoglutarate dehydrogenase in cerebellum of 30-day-old rats. The effect of Prist on DNA damage was also evaluated in blood of these animals. Some parameters were also evaluated in cerebellum from neonatal rats and in cerebellum neuronal cultures. Prist significantly increased malondialdehyde (MDA) levels and carbonyl formation and reduced sulfhydryl content and glutathione (GSH) concentrations in cerebellum of young rats. It also caused DNA strand damage in cerebellum and induced a high micronuclei frequency in blood. On the other hand, this fatty acid significantly reduced α-ketoglutarate dehydrogenase and aconitase activities in rat cerebellum. We also verified that Prist-induced increase of MDA levels was totally prevented by melatonin and attenuated by α-tocopherol but not by the nitric oxide synthase inhibitor N(ω)-nitro-L-arginine methyl ester, indicating the involvement of reactive oxygen species in this effect. Cerebellum from neonate rats also showed marked alterations of redox homeostasis, including an increase of MDA levels and a decrease of sulfhydryl content and GSH concentrations elicited by Prist. Finally, Prist provoked an increase of dichlorofluorescein (DCFH) oxidation in cerebellum-cultivated neurons. Our present data indicate that Prist compromises redox homeostasis in rat cerebellum and blood and inhibits critical enzymes of the citric acid cycle that are susceptible to free radical attack. The present findings may contribute to clarify the pathogenesis of the cerebellar alterations observed in patients affected by ZS and some peroxisomal disorders in which Prist is accumulated.
authors.affiliation: Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600 - Anexo, Porto Alegre, RS, CEP 90035-003, Brazil.
authors.forename: Estela Natacha Brandt
authors.initials: EN
authors.lastname: Busanello
authors.forename: Vannessa Gonçalves Araujo
authors.initials: VG
authors.lastname: Lobato
authors.forename: Ângela
authors.initials: Â
authors.lastname: Zanatta
authors.forename: Clarissa Günther
authors.initials: CG
authors.lastname: Borges
authors.forename: Anelise Miotti
authors.initials: AM
authors.lastname: Tonin
authors.forename: Carolina Maso
authors.initials: CM
authors.lastname: Viegas
authors.forename: Vanusa
authors.initials: V
authors.lastname: Manfredini
authors.forename: César Augusto João
authors.initials: CA
authors.lastname: Ribeiro
authors.forename: Carmen Regla
authors.initials: CR
authors.lastname: Vargas
authors.forename: Diogo Onofre Gomes
authors.initials: DO
authors.lastname: de Souza
authors.forename: Moacir
authors.initials: M
authors.lastname: Wajner
mesh_terms: D000154:Aconitate Hydratase / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D000975:Antioxidants / Q000378:metabolism*; D002478:Cells, Cultured; D002531:Cerebellum / Q000187:drug effects* / Q000378:metabolism*; D004249:DNA Damage / Q000187:drug effects; D005227:Fatty Acids / Q000633:toxicity*; D005452:Fluoresceins / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D006706:Homeostasis / Q000187:drug effects; D007655:Ketoglutarate Dehydrogenase Complex / Q000378:metabolism; D008315:Malondialdehyde / Q000378:metabolism; D008550:Melatonin / Q000008:administration & dosage; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000008:administration & dosage; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects*; D017208:Rats, Wistar; D013438:Sulfhydryl Compounds / Q000378:metabolism; D024502:alpha-Tocopherol / Q000494:pharmacology
chemical_list: D000975:Antioxidants; D005227:Fatty Acids; D005452:Fluoresceins; D018696:Neuroprotective Agents; D013438:Sulfhydryl Compounds; D008315:Malondialdehyde; C037631:2',7'-dichlorofluorescein; C002844:pristanic acid; D019001:Nitric Oxide Synthase; D007655:Ketoglutarate Dehydrogenase Complex; D000154:Aconitate Hydratase; D005978:Glutathione; D024502:alpha-Tocopherol; D008550:Melatonin