title: Chronic administration of branched-chain amino acids impairs spatial memory and increases brain-derived neurotrophic factor in a rat model.
abstract: Maple syrup urine disease (MSUD) is a neurometabolic disorder that leads to the accumulation of branched-chain amino acids (BCAAs) and their α-keto branched-chain by-products. Because the neurotoxic mechanisms of MSUD are poorly understood, this study aimed to evaluate the effects of chronic administration of a BCAA pool (leucine, isoleucine and valine). This study examined the effects of BCAA administration on spatial memory and the levels of brain-derived neurotrophic factor (BNDF). We examined both pro-BDNF and bdnf mRNA expression levels after administration of BCAAs. Furthermore, this study examined whether antioxidant treatment prevented the alterations induced by BCAA administration. Our results demonstrated an increase in BDNF in the hippocampus and cerebral cortex, accompanied by memory impairment in spatial memory tasks. Additionally, chronic administration of BCAAs did not induce a detectable change in pro-BDNF levels. Treatment with N-acetylcysteine and deferoxamine prevented both the memory deficit and the increase in the BDNF levels induced by BCAA administration. In conclusion, these results suggest that when the brain is chronically exposed to high concentrations of BCAA (at millimolar concentrations) an increase in BDNF levels occurs. This increase in BDNF may be related to the impairment of spatial memory. In addition, we demonstrated that antioxidant treatment prevented the negative consequences related to BCAA administration, suggesting that oxidative stress might be involved in the pathophysiological mechanism(s) underlying the brain damage observed in MSUD.
authors.affiliation: Laboratório de Bioenergética, Programa de Pós-Graduação em Ciências da Saúde, Universidade do Extremo Sul Catarinense, Criciuma, SC, Brazil.
authors.forename: Giselli
authors.initials: G
authors.lastname: Scaini
authors.forename: Clarissa M
authors.initials: CM
authors.lastname: Comim
authors.forename: Giovanna M T
authors.initials: GM
authors.lastname: Oliveira
authors.forename: Matheus A B
authors.initials: MA
authors.lastname: Pasquali
authors.forename: João
authors.initials: J
authors.lastname: Quevedo
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Gelain
authors.forename: José Cláudio 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: Maurício R
authors.initials: MR
authors.lastname: Bogo
authors.forename: Emilio L
authors.initials: EL
authors.lastname: Streck
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000597:Amino Acids, Branched-Chain / Q000008:administration & dosage* / Q000378:metabolism / Q000633:toxicity; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism*; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D003676:Deferoxamine / Q000494:pharmacology; D004195:Disease Models, Animal; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D008375:Maple Syrup Urine Disease / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D008568:Memory / Q000187:drug effects*; D008569:Memory Disorders / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000597:Amino Acids, Branched-Chain; D000975:Antioxidants; D019208:Brain-Derived Neurotrophic Factor; D011498:Protein Precursors; D012333:RNA, Messenger; C426674:brain-derived neurotrophic factor precursor; D003676:Deferoxamine; D000111:Acetylcysteine