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Pristanic Acid Provokes Lipid, Protein, and DNA Oxidative Damage and Reduces the Antioxidant Defenses in Cerebellum of Young Rats

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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 Nω-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.

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Acknowledgments

We are grateful to the financial support of CNPq, PROPESq/UFRGS, FAPERGS, PRONEX, FINEP Rede Instituto Brasileiro de Neurociência (IBN-Net) # 01.06.0842-00, Instituto Nacional de Ciência e Tecnologia em Excitotoxicidade e Neuroproteção (INCT-EN), and Programa Nacional de Pós-Doutorado CAPES.

Conflict of Interest

The authors declare that there are no potential conflicts of interest.

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Authors and Affiliations

  1. 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

    Estela Natacha Brandt Busanello, Vannessa Gonçalves Araujo Lobato, Ângela Zanatta, Clarissa Günther Borges, Anelise Miotti Tonin, Carolina Maso Viegas, César Augusto João Ribeiro, Diogo Onofre Gomes de Souza & Moacir Wajner

  2. Programa de Pós-Graduação em Bioquímica, UNIPAMPA, Uruguaiana, RS, Brazil

    Vanusa Manfredini

  3. Serviço de Genética Médica do Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil

    Carmen Regla Vargas & Moacir Wajner

  4. Departamento de Análises, Faculdade de Farmácia, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil

    Carmen Regla Vargas

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  1. Estela Natacha Brandt Busanello
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  2. Vannessa Gonçalves Araujo Lobato
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  3. Ângela Zanatta
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  5. Anelise Miotti Tonin
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Correspondence to Moacir Wajner.

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Busanello, E.N.B., Lobato, V.G.A., Zanatta, Â. et al. Pristanic Acid Provokes Lipid, Protein, and DNA Oxidative Damage and Reduces the Antioxidant Defenses in Cerebellum of Young Rats. Cerebellum 13, 751–759 (2014). https://doi.org/10.1007/s12311-014-0593-0

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