title: Apoptotic signaling pathways induced by acute administration of branched-chain amino acids in an animal model of maple syrup urine disease.
abstract: Maple Syrup Urine Disease (MSUD) is an inborn error of metabolism caused by a deficiency of the branched-chain α-keto acid dehydrogenase complex activity. This blockage leads to accumulation of the branched-chain amino acids leucine, isoleucine and valine, as well as their corresponding α-keto acids and α-hydroxy acids. The affected patients present severe neurological symptoms, such as coma and seizures, as well as edema and cerebral atrophy. Considering that the mechanisms of the neurological symptoms presented by MSUD patients are still poorly understood, in this study, protein levels of apoptotic factors are measured, such as Bcl-2, Bcl-xL, Bax, caspase-3 and -8 in hippocampus and cerebral cortex of rats submitted to acute administration of branched-chain amino acids during their development. The results in this study demonstrated that BCAA acute exposure during the early postnatal period did not significantly change Bcl-2, Bcl-xL, Bax and caspase-8 protein levels. However, the Bax/Bcl-2 ratio and procaspase-3 protein levels were decreased in hippocampus. On the other hand, acute administration of BCAA in 30-day-old rats increase in Bax/Bcl-2 ratio followed by an increased caspase-3 activity in cerebral cortex, whereas BCAA induces apoptosis in hippocampus through activation and cleavage of caspase-3 and -8 without changing the Bax/Bcl-2 ratio. In conclusion, the results suggest that apoptosis could be of pivotal importance in the developmental neurotoxic effects of BCAA. In addition, the current studies also suggest that multiple mechanisms may be involved in BCAA-induced apoptosis in the cerebral cortex and hippocampus.
authors: Laboratório de Bioenergética, Programa de Pós-Graduação em Ciências da Saúde, Universidade do Extremo Sul Catarinense, Av. Universitária, 1105, Criciúma, 88806-000, SC, Brazil.|Instituto Nacional de Ciência e Tecnologia Translacional em Medicina (INCT-TM), Porto Alegre, RS, Brazil.|Núcleo de Excelência em Neurociências Aplicadas de Santa Catarina (NENASC), Florianópolis, Santa Catarina, Brazil.
authors: Thais C
authors: TC
authors: Vilela
authors: Laboratório de Bioenergética, Programa de Pós-Graduação em Ciências da Saúde, Universidade do Extremo Sul Catarinense, Av. Universitária, 1105, Criciúma, 88806-000, SC, Brazil.|Instituto Nacional de Ciência e Tecnologia Translacional em Medicina (INCT-TM), Porto Alegre, RS, Brazil.|Núcleo de Excelência em Neurociências Aplicadas de Santa Catarina (NENASC), Florianópolis, Santa Catarina, Brazil.
authors: Giselli
authors: G
authors: Scaini
authors: Laboratório de Bioenergética, Programa de Pós-Graduação em Ciências da Saúde, Universidade do Extremo Sul Catarinense, Av. Universitária, 1105, Criciúma, 88806-000, SC, Brazil.|Instituto Nacional de Ciência e Tecnologia Translacional em Medicina (INCT-TM), Porto Alegre, RS, Brazil.|Núcleo de Excelência em Neurociências Aplicadas de Santa Catarina (NENASC), Florianópolis, Santa Catarina, Brazil.
authors: Camila B
authors: CB
authors: Furlanetto
authors: Centro de Estudos em Estresse Oxidativo, Departamento de Bioquímica, ICBS, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
authors: Matheus A B
authors: MA
authors: Pasquali
authors: Centro de Estudos em Estresse Oxidativo, Departamento de Bioquímica, ICBS, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
authors: João Paulo A
authors: JP
authors: Santos
authors: Centro de Estudos em Estresse Oxidativo, Departamento de Bioquímica, ICBS, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
authors: Daniel P
authors: DP
authors: Gelain
authors: Centro de Estudos em Estresse Oxidativo, Departamento de Bioquímica, ICBS, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
authors: José Cláudio F
authors: JC
authors: Moreira
authors: Laboratório de Erros Inatos do Metabolismo, Programa de Pós-Graduação em Ciências da Saúde, Universidade do Extremo Sul Catarinense, Criciúma, SC, Brazil.
authors: Patrícia F
authors: PF
authors: Schuck
authors: Laboratório de Neuroquímica, Instituto de Bioquímica Médica, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
authors: Gustavo C
authors: GC
authors: Ferreira
authors: Laboratório de Bioenergética, Programa de Pós-Graduação em Ciências da Saúde, Universidade do Extremo Sul Catarinense, Av. Universitária, 1105, Criciúma, 88806-000, SC, Brazil. emiliostreck@gmail.com.|Instituto Nacional de Ciência e Tecnologia Translacional em Medicina (INCT-TM), Porto Alegre, RS, Brazil. emiliostreck@gmail.com.|Núcleo de Excelência em Neurociências Aplicadas de Santa Catarina (NENASC), Florianópolis, Santa Catarina, Brazil. emiliostreck@gmail.com.
authors: Emilio L
authors: EL
authors: Streck
mesh_terms: D000597:Amino Acids, Branched-Chain / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008375:Maple Syrup Urine Disease / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects*; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D051020:bcl-X Protein / Q000378:metabolism
chemical_list: D000597:Amino Acids, Branched-Chain; C494828:Bax protein, rat; C000617196:Bcl2 protein, rat; C494813:Bcl2l1 protein, rat; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D053148:Caspase 3; D053181:Caspase 8
keywords: Apoptosis; Bcl-2 family members; Branched-chain amino acids; Caspases; Maple syrup urine disease