In Vivo Intracerebral Administration of α-Ketoisocaproic Acid to Neonate Rats Disrupts Brain Redox Homeostasis and Promotes Neuronal Death, Glial Reactivity, and Myelination Injury

Overview

Journal Mol Neurobiol

Specialties Molecular Biology
Neurology

Date 2023 Nov 1

PMID 37910283

Authors

Angela Beatris Zemniacak

Rafael Teixeira Ribeiro

Camila Vieira Pinheiro

Samela de Azevedo Cunha

Tailine Quevedo Tavares

Ediandra Tissot Castro

Guilhian Leipnitz

Moacir Wajner

Alexandre Umpierrez Amaral

Affiliations

Soon will be listed here.

Abstract

Maple syrup urine disease (MSUD) is caused by severe deficiency of branched-chain α-keto acid dehydrogenase complex activity, resulting in tissue accumulation of branched-chain α-keto acids and amino acids, particularly α-ketoisocaproic acid (KIC) and leucine. Affected patients regularly manifest with acute episodes of encephalopathy including seizures, coma, and potentially fatal brain edema during the newborn period. The present work investigated the ex vivo effects of a single intracerebroventricular injection of KIC to neonate rats on redox homeostasis and neurochemical markers of neuronal viability (neuronal nuclear protein (NeuN)), astrogliosis (glial fibrillary acidic protein (GFAP)), and myelination (myelin basic protein (MBP) and 2',3'-cyclic-nucleotide 3'-phosphodiesterase (CNPase)) in the cerebral cortex and striatum. KIC significantly disturbed redox homeostasis in these brain structures 6 h after injection, as observed by increased 2',7'-dichlorofluorescein oxidation (reactive oxygen species generation), malondialdehyde levels (lipid oxidative damage), and carbonyl formation (protein oxidative damage), besides impairing the antioxidant defenses (diminished levels of reduced glutathione and altered glutathione peroxidase, glutathione reductase, and superoxide dismutase activities) in both cerebral structures. Noteworthy, the antioxidants N-acetylcysteine and melatonin attenuated or normalized most of the KIC-induced effects on redox homeostasis. Furthermore, a reduction of NeuN, MBP, and CNPase, and an increase of GFAP levels were observed at postnatal day 15, suggesting neuronal loss, myelination injury, and astrocyte reactivity, respectively. Our data indicate that disruption of redox homeostasis, associated with neural damage caused by acute intracerebral accumulation of KIC in the neonatal period may contribute to the neuropathology characteristic of MSUD patients.

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References

Strauss K, Carson V, Soltys K, Young M, Bowser L, Puffenberger E . Branched-chain α-ketoacid dehydrogenase deficiency (maple syrup urine disease): Treatment, biomarkers, and outcomes. Mol Genet Metab. 2020; 129(3):193-206. DOI: 10.1016/j.ymgme.2020.01.006. View

Chen T, Lu D, Xu F, Ji W, Zhan X, Gao X . Newborn screening of maple syrup urine disease and the effect of early diagnosis. Clin Chim Acta. 2023; 548:117483. DOI: 10.1016/j.cca.2023.117483. View

Li L, Mao X, Yang N, Ji T, Wang S, Ma Y . Identification of gene mutations in six Chinese patients with maple syrup urine disease. Front Genet. 2023; 14:1132364. PMC: 10001893. DOI: 10.3389/fgene.2023.1132364. View

Cheng A, Han L, Feng Y, Li H, Yao R, Wang D . MRI and clinical features of maple syrup urine disease: preliminary results in 10 cases. Diagn Interv Radiol. 2017; 23(5):398-402. PMC: 5602367. DOI: 10.5152/dir.2017.16466. View

Kathait A, Puac P, Castillo M . Imaging Findings in Maple Syrup Urine Disease: A Case Report. J Pediatr Neurosci. 2018; 13(1):103-105. PMC: 5982476. DOI: 10.4103/JPN.JPN_38_17. View

Muelly E, Moore G, Bunce S, Mack J, Bigler D, Morton D . Biochemical correlates of neuropsychiatric illness in maple syrup urine disease. J Clin Invest. 2013; 123(4):1809-20. PMC: 3613932. DOI: 10.1172/JCI67217. View

Schonberger S, Schweiger B, Schwahn B, Schwarz M, Wendel U . Dysmyelination in the brain of adolescents and young adults with maple syrup urine disease. Mol Genet Metab. 2004; 82(1):69-75. DOI: 10.1016/j.ymgme.2004.01.016. View

Taschetto L, Scaini G, Zapelini H, Ramos A, Strapazzon G, Andrade V . Acute and long-term effects of intracerebroventricular administration of α-ketoisocaproic acid on oxidative stress parameters and cognitive and noncognitive behaviors. Metab Brain Dis. 2017; 32(5):1507-1518. DOI: 10.1007/s11011-017-0035-z. View

Wisniewski M, Carvalho-Silva M, Gomes L, Zapelini H, Schuck P, Ferreira G . Intracerebroventricular administration of α-ketoisocaproic acid decreases brain-derived neurotrophic factor and nerve growth factor levels in brain of young rats. Metab Brain Dis. 2015; 31(2):377-83. DOI: 10.1007/s11011-015-9768-8. View

10.

Farias H, Gabriel J, Cecconi M, Lemos I, de Rezende V, Wessler L . The metabolic effect of α-ketoisocaproic acid: in vivo and in vitro studies. Metab Brain Dis. 2020; 36(1):185-192. DOI: 10.1007/s11011-020-00626-y. View

11.

Rabelo F, Lemos I, Dal Toe C, Casagrande D, Freitas M, Quadra M . Acute effects of intracerebroventricular administration of α-ketoisocaproic acid in young rats on inflammatory parameters. Metab Brain Dis. 2023; 38(5):1573-1579. DOI: 10.1007/s11011-023-01193-8. View

12.

Bridi R, Braun C, Zorzi G, Wannmacher C, Wajner M, Lissi E . alpha-keto acids accumulating in maple syrup urine disease stimulate lipid peroxidation and reduce antioxidant defences in cerebral cortex from young rats. Metab Brain Dis. 2005; 20(2):155-67. DOI: 10.1007/s11011-005-4152-8. View

13.

Funchal C, Latini A, Jacques-Silva M, Santos A, Buzin L, Gottfried C . Morphological alterations and induction of oxidative stress in glial cells caused by the branched-chain alpha-keto acids accumulating in maple syrup urine disease. Neurochem Int. 2006; 49(7):640-50. DOI: 10.1016/j.neuint.2006.05.007. View

14.

Patel M, AUERBACH V, Grover W, Wilbur D . Effect of the branched-chain alpha-keto acids on pyruvate metabolism by homogenates of human brain. J Neurochem. 1973; 20(6):1793-6. DOI: 10.1111/j.1471-4159.1973.tb00298.x. View

15.

Ribeiro C, Sgaravatti A, Rosa R, Schuck P, Grando V, Schmidt A . Inhibition of brain energy metabolism by the branched-chain amino acids accumulating in maple syrup urine disease. Neurochem Res. 2007; 33(1):114-24. DOI: 10.1007/s11064-007-9423-9. View

16.

Amaral A, Leipnitz G, Fernandes C, Seminotti B, Schuck P, Wajner M . Alpha-ketoisocaproic acid and leucine provoke mitochondrial bioenergetic dysfunction in rat brain. Brain Res. 2010; 1324:75-84. DOI: 10.1016/j.brainres.2010.02.018. View

17.

Sgaravatti A, Rosa R, Schuck P, Ribeiro C, Wannmacher C, Wyse A . Inhibition of brain energy metabolism by the alpha-keto acids accumulating in maple syrup urine disease. Biochim Biophys Acta. 2003; 1639(3):232-8. DOI: 10.1016/j.bbadis.2003.09.010. View

18.

Bridi R, Araldi J, Sgarbi M, Testa C, Durigon K, Wajner M . Induction of oxidative stress in rat brain by the metabolites accumulating in maple syrup urine disease. Int J Dev Neurosci. 2003; 21(6):327-32. DOI: 10.1016/s0736-5748(03)00074-1. View

19.

Mescka C, Moraes T, Rosa A, Mazzola P, Piccoli B, Jacques C . In vivo neuroprotective effect of L-carnitine against oxidative stress in maple syrup urine disease. Metab Brain Dis. 2011; 26(1):21-8. DOI: 10.1007/s11011-011-9238-x. View

20.

Mescka C, Rosa A, Schirmbeck G, da Rosa T, Catarino F, de Souza L . L-carnitine Prevents Oxidative Stress in the Brains of Rats Subjected to a Chemically Induced Chronic Model of MSUD. Mol Neurobiol. 2015; 53(9):6007-6017. DOI: 10.1007/s12035-015-9500-z. View