title: DNA damage in an animal model of maple syrup urine disease.
abstract: Maple syrup urine disease is an inborn error of metabolism caused by a severe deficiency of the branched chain alpha-ketoacid dehydrogenase complex. Neurological dysfunction is a common finding in patients with maple syrup urine disease. However, the mechanisms underlying the neuropathology of brain damage in this disorder are poorly understood. In this study, we investigated whether acute or chronic administration of a branched chain amino acid pool (leucine, isoleucine and valine) causes transient DNA damage, as determined by the alkaline comet assay, in the brain and blood of rats during development and whether antioxidant treatment prevented the alterations induced by branched chain amino acids. Our results showed that the acute administration of branched chain amino acids increased the DNA damage frequency and damage index in the hippocampus. However, the chronic administration of branched chain amino acids increased the DNA damage frequency and damage index in both the hippocampus and the striatum, and the antioxidant treatment was able to prevent DNA damage in the hippocampus and striatum. The present study demonstrated that metabolite accumulation in MSUD induces DNA damage in the hippocampus and striatum and that it may be implicated in the neuropathology observed in the affected patients. We demonstrated that the effect of antioxidant treatment (N-acetylcysteine plus deferoxamine) prevented DNA damage, suggesting the involvement of oxidative stress in DNA damage.
authors.affiliation: Laboratório de Bioenergética, Programa de Pós-Graduação em Ciências da Saúde, Universidade do Extremo Sul Catarinense, Criciúma, SC, Brazil.
authors.forename: Giselli
authors.initials: G
authors.lastname: Scaini
authors.forename: Isabela C
authors.initials: IC
authors.lastname: Jeremias
authors.forename: Meline O S
authors.initials: MO
authors.lastname: Morais
authors.forename: Gabriela D
authors.initials: GD
authors.lastname: Borges
authors.forename: Bruna P
authors.initials: BP
authors.lastname: Munhoz
authors.forename: Daniela D
authors.initials: DD
authors.lastname: Leffa
authors.forename: Vanessa M
authors.initials: VM
authors.lastname: Andrade
authors.forename: Patrícia F
authors.initials: PF
authors.lastname: Schuck
authors.forename: Gustavo C
authors.initials: GC
authors.lastname: Ferreira
authors.forename: Emilio L
authors.initials: EL
authors.lastname: Streck
mesh_terms: D000597:Amino Acids, Branched-Chain / Q000008:administration & dosage / Q000009:adverse effects; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology / Q000627:therapeutic use; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004249:DNA Damage / Q000187:drug effects; D004195:Disease Models, Animal; D008297:Male; D008375:Maple Syrup Urine Disease / Q000139:chemically induced / Q000188:drug therapy / Q000235:genetics*; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000597:Amino Acids, Branched-Chain; D000975:Antioxidants