title: Coadministration of branched-chain amino acids and lipopolysaccharide causes matrix metalloproteinase activation and blood-brain barrier breakdown.
abstract: Maple syrup urine disease (MSUD) is an inborn error of metabolism caused by a severe deficiency in the activity of the branched-chain α-keto acid dehydrogenase complex, leading to accumulation of the branched-chain amino acids (BCAA) leucine, isoleucine, and valine. Infections have a significant role in precipitating acute metabolic decompensation in patients with MSUD; however, the mechanisms underlying the neurotoxicity in this disorder are poorly understood. In this study, we subjected rats to the coadministration of lipopolysaccharide (LPS), which is a major component of gram-negative bacteria cell walls, and high concentrations of BCAA (H-BCAA) to determine their effects on the permeability of the blood-brain barrier (BBB) and on the levels of matrix metalloproteinases (MMP-2 and MMP-9). Our results demonstrated that the coadministration of H-BCAA and LPS causes breakdown of the BBB and increases the levels of MMP-2 and MMP-9 in the hippocampus of these rats. On the other hand, examination of the cerebral cortex of the 10- and 30-day-old rats revealed a significant difference in Evan's Blue content after coadministration of H-BCAA and LPS, as MMP-9 levels only increased in the cerebral cortex of the 10-day-old rats. In conclusion, these results suggest that the inflammatory process associated with high levels of BCAA causes BBB breakdown. Thus, we suggest that BBB breakdown is relevant to the perpetuation of brain inflammation and may be related to the brain dysfunction observed in MSUD patients.
authors.affiliation: Laboratório de Bioenergética e Núcleo de Excelência em Neurociências Aplicadas de Santa Catarina (NENASC), Programa de Pós-Graduação em Ciências da Saúde, Universidade do Extremo Sul Catarinense, Av. Universitária, 1105, Criciúma, SC, 88806-000, Brazil.
authors.forename: Giselli
authors.initials: G
authors.lastname: Scaini
authors.forename: Meline O S
authors.initials: MO
authors.lastname: Morais
authors.forename: Leticia S
authors.initials: LS
authors.lastname: Galant
authors.forename: Francieli
authors.initials: F
authors.lastname: Vuolo
authors.forename: Dhébora M
authors.initials: DM
authors.lastname: Dall'Igna
authors.forename: Matheus A B
authors.initials: MA
authors.lastname: Pasquali
authors.forename: Vitor M
authors.initials: VM
authors.lastname: Ramos
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Gelain
authors.forename: Jose Claudio F
authors.initials: JC
authors.lastname: Moreira
authors.forename: Patrícia F
authors.initials: PF
authors.lastname: Schuck
authors.forename: Gustavo C
authors.initials: GC
authors.lastname: Ferreira
authors.forename: Francisco G
authors.initials: FG
authors.lastname: Soriano
authors.forename: Felipe
authors.initials: F
authors.lastname: Dal-Pizzol
authors.forename: Emilio L
authors.initials: EL
authors.lastname: Streck
mesh_terms: D000597:Amino Acids, Branched-Chain / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D004789:Enzyme Activation; D006624:Hippocampus / Q000187:drug effects; D007249:Inflammation / Q000188:drug therapy; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D008375:Maple Syrup Urine Disease / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D017208:Rats, Wistar
chemical_list: D000597:Amino Acids, Branched-Chain; D008070:Lipopolysaccharides; D020782:Matrix Metalloproteinases