Abstract
Maple Syrup Urine Disease (MSUD) is an autosomal recessive inborn error of metabolism (IEM), responsible for the accumulation of the branched-chain amino acids (BCAA) leucine, isoleucine, and valine, in addition to their α-keto acids α-ketoisocaproic acid (KIC), α-keto-β-methylvaleric acid (KMV), and α-ketoisovaleric acid (KIV) in the plasma and urine of patients. This process occurs due to a partial or total blockage of the dehydrogenase enzyme activity of branched-chain α-keto acids. Oxidative stress and inflammation are conditions commonly observed on IEM, and the inflammatory response may play an essential role in the pathophysiology of MSUD. We aimed to investigate the acute effect of intracerebroventricular (ICV) administration of KIC on inflammatory parameters in young Wistar rats. For this, sixteen 30-day-old male Wistar rats receive ICV microinjection with 8 µmol KIC. Sixty minutes later, the animals were euthanized, and the cerebral cortex, hippocampus, and striatum structures were collected to assess the levels of pro-inflammatory cytokines (INF-γ; TNF-α, IL-1β). The acute ICV administration of KIC increased INF-γ levels in the cerebral cortex and reduced the levels of INF-γ and TNF-α in the hippocampus. There was no difference in IL-1β levels. KIC was related to changes in the levels of pro-inflammatory cytokines in the brain of rats. However, the inflammatory mechanisms involved in MSUD are poorly understood. Thus, studies that aim to unravel the neuroinflammation in this pathology are essential to understand the pathophysiology of this IEM.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Data Availability
The datasets generated during and/or analyzed during the current study are not publicly available due to ethics reasons but are available from the corresponding author on reasonable request.
References
Amaral AU, Wajner M (2022) Pathophysiology of maple syrup urine disease: focus on the neurotoxic role of the accumulated branched-chain amino acids and branched-chain α-keto acids. Neurochem Int 157:105360. https://doi.org/10.1016/j.neuint.2022.105360
Arisi GM (2014) Nervous and immune systems signals and connections: cytokines in hippocampus physiology and pathology. Epilepsy Behav 38:43-47.?https://doi.org/10.1016/j.yebeh.2014.01017.017
Berry GT, Kaplan PB, Kaye EM et al (2003) MR diffusion imaging and MR spectroscopy of maple syrup urine disease during acute metabolic decompensation. Neuroradiology 45:393–399. https://doi.org/10.1007/s00234-003-0955-7
Bridi R, Braun CA, Zorzi GK et al (2005) α-Keto acids accumulating in maple syrup urine Disease stimulate lipid peroxidation and reduce antioxidant defences in cerebral cortex from young rats. Metab Brain Dis 20:155–167. https://doi.org/10.1007/s11011-005-4152-8
Calder PC (2006) Branched-chain amino acids and immunity. J Nutr 136. https://doi.org/10.1093/jn/136.1.288S. :288S-293S
Chuang D, Shih V (2001) Maple syrup urine disease (branched-chain ketoaciduria). The metabolic and molecular bases of inherited disease. McGrawHill, New York
Chuang D, wYNN M, Shih V (2008) Doença da urina do xarope de bordo (cetoacidúria de cadeia ramificada). As bases metabólicas e moleculares da doença hereditária. McGrawHill, Nova York, pp 1971–2005
Colonna M, Butovsky O (2017) Microglia function in the Central Nervous System during Health and Neurodegeneration. Annu Rev Immunol 35:441–468. https://doi.org/10.1146/annurev-immunol-051116-052358
Dancis J, Hutzler J, Snyderman SE, Cox RP (1972) Enzyme activity in classical and variant forms of maple syrup urine disease. J Pediatr 81:312–320. https://doi.org/10.1016/S0022-3476(72)80301-9
de Castro Vasques V, Avila de Boer M, Diligenti F et al (2004) Intrahippocampal administration of the α-keto acids accumulating in maple syrup urine disease provokes learning deficits in rats. Pharmacol Biochem Behav 77:183–190. https://doi.org/10.1016/j.pbb.2003.10.013
De Simone R, Vissicchio F, Mingarelli C et al (2013) Branched-chain amino acids influence the immune properties of microglial cells and their responsiveness to pro-inflammatory signals. Biochim et Biophys Acta (BBA) - Mol Basis Disease 1832:650–659. https://doi.org/10.1016/j.bbadis.2013.02.001
Deon M, Sitta A, Faverzani JL et al (2015) Urinary biomarkers of oxidative stress and plasmatic inflammatory profile in phenylketonuric treated patients. Int j dev neurosci 47:259–265. https://doi.org/10.1016/j.ijdevneu.2015.10.001
Di Benedetto S, Müller L, Wenger E et al (2017) Contribution of neuroinflammation and immunity to brain aging and the mitigating effects of physical and cognitive interventions. Neurosci Biobehavioral Reviews 75:114–128. https://doi.org/10.1016/j.neubiorev.2017.01.044
Farias HR, Gabriel JR, Cecconi ML et al (2021) The metabolic effect of α-ketoisocaproic acid: in vivo and in vitro studies. Metab Brain Dis 36:185–192. https://doi.org/10.1007/s11011-020-00626-y
Funchal C, Latini A, Jacques-Silva MC et al (2006) Morphological alterations and induction of oxidative stress in glial cells caused by the branched-chain α-keto acids accumulating in maple syrup urine disease. Neurochem Int 49:640–650. https://doi.org/10.1016/j.neuint.2006.05.007
Gelders G, Baekelandt V, Van der Perren A (2018) Linking neuroinflammation and neurodegeneration in Parkinson’s Disease. J Immunol Res 2018:1–12. https://doi.org/10.1155/2018/4784268
Jain P, Sharma S, Sankhyan N et al (2013) Imaging in neonatal maple syrup urine disease. Indian J Pediatr 80:87–88. https://doi.org/10.1007/s12098-012-0850-5
Klee D, Thimm E, Wittsack HJ et al (2013) Structural white matter changes in adolescents and young adults with maple syrup urine disease. J Inherit Metab Dis 36:945–953. https://doi.org/10.1007/s10545-012-9582-y
Lugrin J, Rosenblatt-Velin N, Parapanov R, Liaudet L (2014) The role of oxidative stress during inflammatory processes. Biol Chem 395:203–230. https://doi.org/10.1515/hsz-2013-0241
Menkes JH (1959) Maple syrup disease; isolation and identification of organic acids in the urine. Pediatrics 23:348–353
Mescka C, Moraes T, Rosa A et al (2011) In vivo neuroprotective effect of L-carnitine against oxidative stress in maple syrup urine disease. Metab Brain Dis 26:21–28. https://doi.org/10.1007/s11011-011-9238-x
Mescka CP, Guerreiro G, Donida B et al (2015a) Investigation of inflammatory profile in MSUD patients: benefit of L-carnitine supplementation. Metab Brain Dis 30:1167–1174. https://doi.org/10.1007/s11011-015-9686-9
Mescka CP, Guerreiro G, Hammerschmidt T et al (2015b) l-Carnitine supplementation decreases DNA damage in treated MSUD patients. Mutat Research/Fundamental Mol Mech Mutagen 775:43–47. https://doi.org/10.1016/j.mrfmmm.2015.03.008
Muhammad M (2020) Tumor Necrosis Factor Alpha: A Major Cytokine of Brain Neuroinflammation. In: Behzadi P (ed) Cytokines. IntechOpen
Muralidharan S, Mandrekar P (2013) Cellular stress response and innate immune signaling: integrating pathways in host defense and inflammation. J Leukoc Biol 94:1167–1184. https://doi.org/10.1189/jlb.0313153
Niranjan R (2013) Molecular basis of Etiological Implications in Alzheimer’s Disease: Focus on Neuroinflammation. Mol Neurobiol 48:412–428. https://doi.org/10.1007/s12035-013-8428-4
Olmos G, Lladó J (2014) Tumor necrosis factor alpha: a link between Neuroinflammation and Excitotoxicity. Mediat Inflamm 2014:1–12. https://doi.org/10.1155/2014/861231
Opal SM, DePalo VA (2000) Anti-inflammatory cytokines. Chest 117:1162–1172. https://doi.org/10.1378/chest.117.4.1162
Paxinos G, Watson C (1986) The rat brain in stereotaxic coordinates. Academic Press, Sydney
Ribeiro CA, Sgaravatti ÂM, Rosa RB et al (2008) Inhibition of Brain Energy metabolism by the branched-chain amino acids accumulating in maple syrup urine disease. Neurochem Res 33:114–124. https://doi.org/10.1007/s11064-007-9423-9
Ribeiro LR, Della-Pace ID, de Oliveira Ferreira AP et al (2013) Chronic administration of methylmalonate on young rats alters neuroinflammatory markers and spatial memory. Immunobiology 218:1175–1183. https://doi.org/10.1016/j.imbio.2013.04.008
Ronald Zielke H, Zielke CL, Baab PJ, Collins RM (2002) Large neutral amino acids auto exchange when infused by microdialysis into the rat brain: implication for maple syrup urine disease and phenylketonuria. Neurochem Int 40:347–354. https://doi.org/10.1016/S0197-0186(01)00077-8
Rosa L, Scaini G, Furlanetto CB et al (2016) Administration of branched-chain amino acids alters the balance between pro‐inflammatory and anti‐inflammatory cytokines. Int j dev neurosci 48:24–30. https://doi.org/10.1016/j.ijdevneu.2015.11.002
Scaini G, Tonon T, de Souza CFM et al (2017) Serum markers of neurodegeneration in maple syrup urine disease. Mol Neurobiol 54:5709–5719. https://doi.org/10.1007/s12035-016-0116-8
Scaini G, Tonon T, Moura de Souza CF et al (2018) Evaluation of plasma biomarkers of inflammation in patients with maple syrup urine disease. J Inherit Metab Dis 41:631–640. https://doi.org/10.1007/s10545-018-0188-x
Schonberger S (2004) Dysmyelination in the brain of adolescents and young adults with maple syrup urine disease. Mol Genet Metab 82:69–75. https://doi.org/10.1016/j.ymgme.2004.01.016
Seminotti B, Amaral AU, Ribeiro RT et al (2016) Oxidative stress, disrupted Energy Metabolism, and altered signaling pathways in Glutaryl-CoA dehydrogenase knockout mice: potential implications of quinolinic acid toxicity in the neuropathology of Glutaric Acidemia Type I. Mol Neurobiol 53:6459–6475. https://doi.org/10.1007/s12035-015-9548-9
Sgaravatti AM, Rosa RB, Schuck PF et al (2003) Inhibition of brain energy metabolism by the α-keto acids accumulating in maple syrup urine disease. Biochimica et Biophysica Acta (BBA) -. Mol Basis Disease 1639:232–238. https://doi.org/10.1016/j.bbadis.2003.09.010
Sitta A, Ribas GS, Mescka CP et al (2014) Neurological damage in MSUD: the role of oxidative stress. Cell Mol Neurobiol 34:157–165. https://doi.org/10.1007/s10571-013-0002-0
Snyderman SE, Norton PM, Roitman E, Holt LE (1964) MAPLE SYRUP URINE DISEASE, WITH PARTICULAR REFERENCE TO DIETOTHERAPY. Pediatrics 34:454–472
Stephenson J, Nutma E, van der Valk P, Amor S (2018) Inflammation in CNS neurodegenerative diseases. Immunology 154:204–219. https://doi.org/10.1111/imm.12922
Taschetto L, Scaini G, Zapelini HG et al (2017) Acute and long-term effects of intracerebroventricular administration of α-ketoisocaproic acid on oxidative stress parameters and cognitive and noncognitive behaviors. Metab Brain Dis 32:1507–1518. https://doi.org/10.1007/s11011-017-0035-z
Tavares RG, Santos CES, Tasca CI et al (2000) Inhibition of glutamate uptake into synaptic vesicles of rat brain by the metabolites accumulating in maple syrup urine disease. J Neurol Sci 181:44–49. https://doi.org/10.1016/S0022-510X(00)00402-0
Teleanu DM, Niculescu A-G, Lungu II et al (2022) An overview of oxidative stress, Neuroinflammation, and neurodegenerative Diseases. IJMS 23:5938. https://doi.org/10.3390/ijms23115938
Treacy E, Clow CL, Reade TR et al (1992) Maple syrup urine disease: interrelations between branched-chain amino‐, oxo‐ and hydroxyacids; implications for treatment; associations with CNS dysmyelination. J of Inher Metab Disea 15:121–135. https://doi.org/10.1007/BF01800354
Varella PPV, Forte WCN (2001) Citokines: a review. Rev bras alergia imunopatol 24:146–154
Vivekanantham S, Shah S, Dewji R et al (2015) Neuroinflammation in Parkinson’s disease: role in neurodegeneration and tissue repair. Int J Neurosci 125:717–725. https://doi.org/10.3109/00207454.2014.982795
Wajner M, Coelho DM, Barschak AG et al (2000) Reduction of large neutral amino acid concentrations in plasma and CSF of patients with maple syrup urine disease during crises. J Inherit Metab Dis 23:505–512. https://doi.org/10.1023/A:1005668431926
Wasim M, Awan FR, Khan HN et al (2018) Aminoacidopathies: prevalence, etiology, screening, and Treatment Options. Biochem Genet 56:7–21. https://doi.org/10.1007/s10528-017-9825-6
Wessler LB, Miranda Ramos V, Bittencourt Pasquali MA et al (2019) Administration of branched-chain amino acids increases the susceptibility to lipopolysaccharide‐induced inflammation in young Wistar rats. Int j dev neurosci 78:210–214. https://doi.org/10.1016/j.ijdevneu.2019.07.007
Wisniewski MSW, Carvalho-Silva M, Gomes LM et al (2016) Intracerebroventricular administration of α-ketoisocaproic acid decreases brain-derived neurotrophic factor and nerve growth factor levels in brain of young rats. Metab Brain Dis 31:377–383. https://doi.org/10.1007/s11011-015-9768-8
Zinnanti WJ, Lazovic J, Griffin K et al (2008) Dual mechanism of brain injury and novel treatment strategy in maple syrup urine disease. Brain 132:903–918. https://doi.org/10.1093/brain/awp024
Acknowledgements
This research was supported by grants from Universidade do Extremo Sul Catarinense (UNESC), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) and Fundação de Amparo à Pesquisa e Inovação do Estado de Santa Catarina.
Funding
This research was supported by grants from Universidade do Extremo Sul Catarinense (UNESC), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) and Fundação de Amparo à Pesquisa e Inovação do Estado de Santa Catarina.
Author information
Authors and Affiliations
Contributions
FR and ELS developed the study conception and design. ISL, CPDT, DDC and MLSF performed the experiment. IRL, MM, PCLS and FDP carried out the data analysis. FR, ISL and ELS developed the statistical analysis. The first draft of the manuscript was written by FR and MRQ. JSG and ELS conducted the written review. All authors read and approved the final manuscript.
Corresponding author
Ethics declarations
Competing interests
None.
Ethics approval
All experimental procedures were approved by the UNESC ethics committee (protocol number 23/2021), following the recommend dations of the National Institutes of Health Guide for the Care and Use of Laboratory Animals and the Brazilian Society of Neurosciences and Behavior for animal care.
Consent to participate
Not applicable.
Consent to publish
Not applicable.
Additional information
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Rabelo, F., Lemos, I.d.S., Dal Toé, C.P. et al. Acute effects of intracerebroventricular administration of α-ketoisocaproic acid in young rats on inflammatory parameters. Metab Brain Dis 38, 1573–1579 (2023). https://doi.org/10.1007/s11011-023-01193-8
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11011-023-01193-8