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01.09.2013 | Original Article

Chronic administration of branched-chain amino acids impairs spatial memory and increases brain-derived neurotrophic factor in a rat model

verfasst von: Giselli Scaini, Clarissa M. Comim, Giovanna M. T. Oliveira, Matheus A. B. Pasquali, João Quevedo, Daniel P. Gelain, José Cláudio F. Moreira, Patrícia F. Schuck, Gustavo C. Ferreira, Maurício R. Bogo, Emilio L. Streck

Erschienen in: Journal of Inherited Metabolic Disease | Ausgabe 5/2013

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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.

Bekinschtein P, Cammarota M, Izquierdo I, Medina JH (2007) BDNF and memory formation and storage. Neuroscientist 14:147–156CrossRefPubMed

Bekinschtein P, Cammarota M, Katche C et al (2008) BDNF is essential to promote persistence of long-term memory storage. Proc Natl Acad Sci U S A 105:2711–2716CrossRefPubMedPubMedCentral

Bonhoeffer T (1996) Neurotrophins and activity-dependent development of the neocortex. Curr Opin Neurobiol 6:119–126CrossRefPubMed

Boyd JG, Gordon T (2002) A dose-dependent facilitation and inhibition of peripheral nerve regeneration by brain-derived neurotrophic factor. Eur J Neurosci 15:613–626CrossRefPubMed

Bridi R, Araldi J, Sgarbi MB et al (2003) Induction of oxidative stress in rat brain by the metabolites accumulating in maple syrup urine disease. Int J Dev Neurosci 21:327–332CrossRefPubMed

Bridi R, Latini A, Braun CA (2005) Evaluation of the mechanisms involved in leucine induced oxidative damage in cerebral cortex of young rats. Free Radic Res 39:71–79CrossRefPubMed

Bridi R, Fontella FU, Pulrolnik V et al (2006) A chemically-induced acute model of maple syrup urine disease in rats for neurochemical studies. J Neurosci Methods 155:224–230CrossRefPubMed

Brown RE, Corey SC, Moore AK (1999) Differences in measures of exploration and fear in MHC-congenic C57BL/6J and B6-H-2K mice. Behav Genet 26:263–271CrossRef

Castellano S, Macchi F, Scali M, Huang JZ, Bozzi Y (2006) Cytosolic branched chain aminotransferase (BCATc) mRNA is up-regulated in restricted brain areas of BDNF transgenic mice. Brain Res 1108:12–18CrossRefPubMed

Chuang DT, Shih VE (2001) Maple syrup urine disease (branchedchain ketoaciduria). In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds) The metabolic and molecular bases of inherited disease. McGraw-Hill, New York, pp 1971–2005

Croll SD, Suri C, Compton DL (1999) Brain-derived neurotrophic factor transgenic mice exhibit passive avoidance deficits, increased seizure severity and in vitro hyperexcitability in the hippocampus and entorhinal cortex. Neuroscience 93:1491–1506CrossRefPubMedPubMedCentral

Cunha C, Angelucci A, D’Antoni A (2009) Brain-derived neurotrophic factor (BDNF) overexpression in the forebrain results in learning and memory impairments. Neurobiol Dis 33:358–368CrossRefPubMed

da Silva RS, Richetti SK, da Silveira VG (2008) Maternal caffeine intake affects acetylcholinesterase in hippocampus of neonate rats. Int J Dev Neurosci 26:339–343CrossRefPubMed

Danner DJ, Elsas LJ (1989) Disorders of branched chain amino acid and keto acid metabolism. In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds) The metabolic basis of inherited disease. McGraw-Hill, New York, pp 671–692

Di-Pietro PB, Dias ML, Scaini G (2008) Inhibition of brain creatine kinase activity after renal ischemia is attenuated by N-acetylcysteine and deferoxamine administration. Neurosci Lett 434:139–143CrossRefPubMed

Figurov A, Pozzo-Miller LD, Olafsson P, Wang T, Lu B (1996) Regulation of synaptic responses to high-frequency stimulation and LTP by neurotrophins in the hippocampus. Nature 381:706–709CrossRefPubMed

Fontella FU, Gassen E, Pulrolni V (2002) Stimulation of lipid peroxidation in vitro in rat brain by the metabolites accumulating in maple syrup urine disease. Metab Brain Dis 17:47–54CrossRefPubMed

Glaser V, Carlini VP, Gabach L (2010) The intra-hippocampal leucine administration impairs memory consolidation and LTP generation in rats. Cell Mol Neurobiol 30:1067–1075CrossRefPubMed

Gwag BJ, Koh JY, Chen MM (1995) BDNF or IGF-I potentiates free radical-mediated injury in cortical cell cultures. Neuroreport 7:93–96CrossRefPubMed

Haddad JJ, Land SC (2002) Redox/ROS regulation of lipopolysaccharide-induced mitogen-activated protein kinase (MAPK) activation and MAPK-mediated TNF-alpha biosynthesis. Br J Pharmacol 135:520–536CrossRefPubMedPubMedCentral

Howell RK, Lee M (1963) Influence of a-keto acids on the respiration of brain in vitro. Proc Soc Exp Biol Med 113:660–663CrossRefPubMed

Huang EJ, Reichardt LF (2001) Neurotrophins: roles in neuronal development and function. Annu Rev Neurosci 24:677–736CrossRefPubMedPubMedCentral

Huang EJ, Reichardt LF (2003) Trk receptors: roles in neuronal signal transduction. Annu Rev Biochem 72:609–642CrossRefPubMed

Ishikawa Y, Ikeuchi T, Hatanaka H (2000) Brain-derived neurotrophic factor accelerates nitric oxide donor-induced apoptosis of cultured cortical neurons. J Neurochem 75:494–502CrossRefPubMed

Jouvet J, Rustin P, Taylor DL (2000) Branched chain amino acids induce apoptosis in neural cells without mitochondrial membrane depolarization or cytochrome c release: Implications for neurological impairment associated with maple syrup urine disease. Mol Biol Cell 11:1919–1932CrossRefPubMedPubMedCentral

Kim SH, Won SJ, Sohn S, Kwon HJ, Lee JY, Park JH, Gwag BJ (2002) Brain-derived neurotrophic factor can act as a pronecrotic factor through transcriptional and translational activation of NADPH oxidase. J Cell Biol 159821–159831

Koh JY, Gwag BJ, Lobner D, Choi DW (1995) Potentiated necrosis of cultured cortical neurons by neurotrophins. Science 268:573–575CrossRefPubMed

Korte M, Carroll P, Wolf E, Brem G, Thoenen H, Bonhoeffer T (1995) Hippocampal long-term potentiation is impaired in mice lacking brainderived neurotrophic factor. Proc Natl Acad Sci U S A 92:8856–8860CrossRefPubMedPubMedCentral

Kubo T, Nonomura T, Enokido Y, Hatanaka H (1995) Brainderived neurotrophic factor (BDNF) can prevent apoptosis of rat cerebellar granule neurons in culture. Brain Res Dev Brain Res 85:249–258CrossRefPubMed

Land JM, Mowbray J, Clark JB (1976) Control of pyruvate and h-hydroxybutyrate utilization in rat brain mitochondria and its relevance to phenylketonuria and maple syrup urine disease. J Neurochem 26:823–830CrossRefPubMed

Lee R, Kermani P, Teng KK, Hempstead BL (2001) Regulation of cell survival by secreted proneurotrophins. Science 294:1945–1948CrossRefPubMed

Lewin GR, Barde YA (1996) Physiology of the neurotrophins. Annu Rev Neurosci 19:289–317CrossRefPubMed

Lowry OH, Rosebough NG, Farr AL, Randall RJ (1951) Protein measurement with the Folin phenol reagent. J Chem Biol 193:265–275

Lu B, Pang PT, Woo NH (2005) The yin and yang of neurotrophin action. Nat Rev Neurosci 6:603–614CrossRefPubMed

Lu Y, Christian K, Lu B (2008) BDNF: a key regulator for protein synthesis-dependent LTP and longterm memory? Neurobiol Learn Mem 89:312–323CrossRefPubMed

Mackenzie DY, Woolf LI (1959) Maple syrup urine disease; an inborn error of the metabolism of valine, leucine, and isoleucine associated with gross mental deficiency. Br Med J 1:90–91CrossRefPubMedPubMedCentral

Mello CF, Feksa L, Brusque AM, Wannmacher CM, Wajner M (1999) Chronic early leucine administration induces behavioral deficits in rats. Life Sci 65:747–755CrossRefPubMed

Mescka C, Moraes T, Rosa A (2011) In vivo neuroprotective effect of L-carnitine against oxidative stress in maple syrup urine disease. Metab Brain Dis 26:21–28CrossRefPubMed

Nitta A, Nishioka H, Fukumitsu H (2004) Hydrophobic dipeptide LeueIle protects against neuronal death by inducing brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor synthesis. J Neurosci Res 78:250–258CrossRefPubMed

Nonomura T, Kubo T, Oka T (1996) Signaling pathways and survival effects of BDNF and NT-3 on cultured cerebellar granule cells. Brain Res Dev Brain Res 97:42–50CrossRefPubMed

Patterson SL, Abel T, Deuel TA, Martin KC, Rose JC, Kandel ER (1996) Recombinant BDNF rescues deficits in basal synaptic transmission and hippocampal LTP in BDNF knockout mice. Neuron 16:1137–1145CrossRefPubMed

Pilla C, Cardozo RF, Dutra-Filho CS, Wyse AT, Wajner M, Wannmacher CM (2003) Creatine kinase activity from rat brain is inhibited by branched-chain amino acids in vitro. Neurochem Res 28:675–679CrossRefPubMed

Poo MM (2001) Neurotrophins as synaptic modulators. Nat Rev Neurosci 2:24–32CrossRefPubMed

Ribeiro CA, Sgaravatti AM, Rosa R (2008) Inhibition of brain energy metabolism by the branched-chain amino acids accumulating in maple syrup urine disease. Neurochem Res 33:114–124CrossRefPubMed

Rosa RM, Flores DG, Appelt HR, Braga AL, Henriques JA, Roesler R (2003) Facilitation of long-term object recognition memory by pretraining administration of diphenyl diselenide in mice. Neurosci Lett 341:217–220CrossRefPubMed

Scaini G, Teodorak BP, Jeremias IC (2012) Antioxidant administration prevents memory impairment in an animal model of maple syrup urine disease. Behav Brain Res 23:92–96CrossRef

Schroder N, O’Dell SJ, Marshall JF (2003) Neurotoxic methamphetamine regimen severely impairs recognition memory in rats. Synapse 49:89–96CrossRefPubMed

Sgaravati AM, Rosa RB, Schuck PF (2003) Inhibition of brain energy metabolism by the a-keto acids accumulating in maple syrup urine disease. Biochim Biophys Acta 1639:232–238CrossRef

Snider WD (1994) Functions of the neurotrophins during nervous system development: what the knockouts are teaching us. Cell 77:627–638CrossRefPubMed

Snyderman SE, Norton PM, Roitman E, Holt LE Jr (1964) Maple syrup urine disease, with particular reference to dietotherapy. Pediatrics 34:454–472PubMed

Soule J, Messaoudi E, Bramham CR (2006) Brain-derived neurotrophic factor and control of synaptic consolidation in the adult brain. Biochem Soc Trans 34:600–604CrossRefPubMed

Taketomi T, Kunishita T, Hara A, Mizushima S (1983) Abnormal protein and lipid compositions of the cerebral myelin of a patient with maple syrup urine disease. Jpn J Exp Med 53:109–116PubMed

Thoenen H (1995) Neurotrophins and neuronal plasticity. Science 270:593–598CrossRefPubMed

Treacy E, Clow CL, Reade TR, Chitayat D, Mamer OA, Scriver CR (1992) Maple syrup urine disease: interrelationship between branched-chain amino-, oxo- and hydroxyacids; implications for treatment; associations with CNS dysmyelination. J Inherit Metab Dis 15:121–135CrossRefPubMed

Tribble D, Shapira R (1983) Myelin proteins: degradation in rat brain initiated by metabolites causative of maple syrup urine disease. Biochem Biophys Res Commun 114:440–446CrossRefPubMed

Tyler WJ, Alonso M, Bramham CR, Pozzo-Miller LD (2002) From acquisition to consolidation: on the role of brain-derived neurotrophic factor signaling in hippocampal-dependent learning. Learn Mem 9:224–237CrossRefPubMedPubMedCentral

Vasques VC, Brinco F, Wajner M (2005) Intrahippocampal administration of the branched-chain alpha-hydroxy acids accumulating in maple syrup urine disease compromises rat performance in aversive and non-aversive behavioral tasks. J Neurol Sci 232:11–21CrossRef

Vianna MR, Alonso M, Viola H (2000) Role of hippocampal signaling pathways in long-term memory formation of a nonassociative learning task in the rat. Learn Mem 7:333–340CrossRefPubMedPubMedCentral

Woo NH, Teng HK, Siao CJ (2005) Activation of p75NTR by proBDNF facilitates hippocampal long-term depression. Nat Neurosci 8:1069–1077CrossRefPubMed

Yamada K, Mizuno M, Nabeshima T (2002) Role for brain-derived neurotrophic factor in learning and memory. Life Sci 70:735–744CrossRefPubMed

Titel: Chronic administration of branched-chain amino acids impairs spatial memory and increases brain-derived neurotrophic factor in a rat model
verfasst von: Giselli Scaini
Clarissa M. Comim
Giovanna M. T. Oliveira
Matheus A. B. Pasquali
João Quevedo
Daniel P. Gelain
José Cláudio F. Moreira
Patrícia F. Schuck
Gustavo C. Ferreira
Maurício R. Bogo
Emilio L. Streck
Publikationsdatum: 01.09.2013
Verlag: Springer Netherlands
Erschienen in: Journal of Inherited Metabolic Disease / Ausgabe 5/2013
Print ISSN: 0141-8955
Elektronische ISSN: 1573-2665
DOI: https://doi.org/10.1007/s10545-012-9549-z

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