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Bezafibrate In Vivo Administration Prevents 3-Methylglutaric Acid-Induced Impairment of Redox Status, Mitochondrial Biogenesis, and Neural Injury in Brain of Developing Rats

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Abstract

3-Methylglutaric acid (MGA) is an organic acid that accumulates in 3-methylglutaconic (MGTA) and 3-hydroxy-3-methylglutaric (HMGA) acidurias. Patients affected by these disorders present with neurological dysfunction that usually appears in the first years of life. In order to elucidate the pathomechanisms underlying the brain injury in these disorders, we evaluated the effects of MGA administration on redox homeostasis, mitochondrial respiratory chain activity, and biogenesis in the cerebral cortex of developing rats. Neural damage markers and signaling pathways involved in cell survival, and death were also measured after MGA administration. Furthermore, since the treatment for MGTA and HMGA is still limited, we tested whether a pre-treatment with the pan-peroxisome proliferator-activated receptor (PPAR) agonist bezafibrate could prevent the alterations caused by MGA. MGA provoked lipid peroxidation, increased heme oxygenase-1 content, and altered the activities of antioxidant enzymes, strongly suggestive of oxidative stress. MGA also impaired mitochondrial function and biogenesis by decreasing the activities of succinate dehydrogenase and various respiratory chain complexes, as well as the nuclear levels of PGC-1α and NT-PGC-1α, and cell content of Sirt1. AMPKα1 was further increased by MGA. Neural cell damage was also observed following the MGA administration, as verified by decreased Akt and synaptophysin content and reduced ERK phosphorylation, and by the increase of active caspase-3 and p38 and Tau phosphorylation. Importantly, bezafibrate prevented MGA-elicited toxic effects towards mitochondrial function, redox homeostasis, and neural cell injury, implying that this compound may be potentially used as an adjunct therapy for MGTA and HMGA and other disorders with mitochondrial dysfunction.

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References

  • Aebi H (1984) Catalase in vitro. Methods Enzymol 105:121–126

    Article  CAS  Google Scholar 

  • Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72:248–254

    Article  CAS  Google Scholar 

  • Carlberg I, Mannervik B (1985) Glutathione reductase. Methods Enzymol 113:484–490

    Article  CAS  Google Scholar 

  • Chandra A, Sharma A, Calingasan NY, White JM, Shurubor Y, Yang XW, Beal MF, Johri A (2016) Enhanced mitochondrial biogenesis ameliorates disease phenotype in a full-length mouse model of Huntington’s disease. Hum Mol Genet 25:2269–2282. https://doi.org/10.1093/hmg/ddw095

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chatzispyrou IA, Guerrero-Castillo S, Held NM, Ruiter JPN, Denis SW, L IJ, Wanders RJ, van Weeghel M, Ferdinandusse S, Vaz FM, Brandt U, Houtkooper RH (2018) Barth syndrome cells display widespread remodeling of mitochondrial complexes without affecting metabolic flux distribution. Biochim Biophys Acta Mol basis Dis 1864:3650–3658. https://doi.org/10.1016/j.bbadis.2018.08.041

    Article  CAS  PubMed  Google Scholar 

  • Colin-Gonzalez AL, Paz-Loyola AL, de Lima ME, Galvan-Arzate S, Seminotti B, Ribeiro CA, Leipnitz G, Souza DO, Wajner M, Santamaria A (2016) Experimental evidence that 3-methylglutaric acid disturbs mitochondrial function and induced oxidative stress in rat brain synaptosomes: new converging mechanisms. Neurochem Res 41:2619–2626. https://doi.org/10.1007/s11064-016-1973-2

    Article  CAS  PubMed  Google Scholar 

  • da Rosa MS, Seminotti B, Amaral AU, Fernandes CG, Gasparotto J, Moreira JC, Gelain DP, Wajner M, Leipnitz G (2013) Redox homeostasis is compromised in vivo by the metabolites accumulating in 3-hydroxy-3-methylglutaryl-coa lyase deficiency in rat cerebral cortex and liver. Free Radic Res 47:1066–1075. https://doi.org/10.3109/10715762.2013.853876

    Article  CAS  PubMed  Google Scholar 

  • da Rosa MS, Seminotti B, Ribeiro CA, Parmeggiani B, Grings M, Wajner M, Leipnitz G (2016) 3-hydroxy-3-methylglutaric and 3-methylglutaric acids impair redox status and energy production and transfer in rat heart: relevance for the pathophysiology of cardiac dysfunction in 3-hydroxy-3-methylglutaryl-coenzyme a lyase deficiency. Free Radic Res 50:997–1010. https://doi.org/10.1080/10715762.2016.1214952

    Article  CAS  PubMed  Google Scholar 

  • da Silva CG, Ribeiro CA, Leipnitz G, Dutra-Filho CS, Wyse AA, Wannmacher CM, Sarkis JJ, Jakobs C, Wajner M (2002) Inhibition of cytochrome c oxidase activity in rat cerebral cortex and human skeletal muscle by d-2-hydroxyglutaric acid in vitro. Biochim Biophys Acta 1586:81–91

    Article  PubMed  Google Scholar 

  • Dineley KT, Westerman M, Bui D, Bell K, Ashe KH, Sweatt JD (2001) Beta-amyloid activates the mitogen-activated protein kinase cascade via hippocampal alpha7 nicotinic acetylcholine receptors: in vitro and in vivo mechanisms related to Alzheimer’s disease. J Neurosci 21:4125–4133

    Article  CAS  PubMed  Google Scholar 

  • Distelmaier F, Valsecchi F, Liemburg-Apers DC, Lebiedzinska M, Rodenburg RJ, Heil S, Keijer J, Fransen J, Imamura H, Danhauser K, Seibt A, Viollet B, Gellerich FN, Smeitink JA, Wieckowski MR, Willems PH, Koopman WJ (2015) Mitochondrial dysfunction in primary human fibroblasts triggers an adaptive cell survival program that requires ampk-alpha. Biochim Biophys Acta 1852:529–540. https://doi.org/10.1016/j.bbadis.2014.12.012

    Article  CAS  PubMed  Google Scholar 

  • Dumont M, Stack C, Elipenahli C, Jainuddin S, Gerges M, Starkova N, Calingasan NY, Yang L, Tampellini D, Starkov AA, Chan RB, Di Paolo G, Pujol A, Beal MF (2012) Bezafibrate administration improves behavioral deficits and tau pathology in p301s mice. Hum Mol Genet 21:5091–5105. https://doi.org/10.1093/hmg/dds355

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Engelen M, Schackmann MJ, Ofman R, Sanders RJ, Dijkstra IM, Houten SM, Fourcade S, Pujol A, Poll-The BT, Wanders RJ, Kemp S (2012) Bezafibrate lowers very long-chain fatty acids in x-linked adrenoleukodystrophy fibroblasts by inhibiting fatty acid elongation. J Inherit Metab Dis 35:1137–1145. https://doi.org/10.1007/s10545-012-9471-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Evelson P, Travacio M, Repetto M, Escobar J, Llesuy S, Lissi EA (2001) Evaluation of total reactive antioxidant potential (trap) of tissue homogenates and their cytosols. Arch Biochem Biophys 388:261–266. https://doi.org/10.1006/abbi.2001.2292

    Article  CAS  PubMed  Google Scholar 

  • Fernandes CG, Rodrigues MDN, Seminotti B, Colin-Gonzalez AL, Santamaria A, Quincozes-Santos A, Wajner M (2016) Induction of a proinflammatory response in cortical astrocytes by the major metabolites accumulating in hmg-coa lyase deficiency: the role of erk signaling pathway in cytokine release. Mol Neurobiol 53:3586–3595. https://doi.org/10.1007/s12035-015-9289-9

    Article  CAS  PubMed  Google Scholar 

  • Ferri L, Dionisi-Vici C, Taurisano R, Vaz FM, Guerrini R, Morrone A (2016) When silence is noise: infantile-onset Barth syndrome caused by a synonymous substitution affecting taz gene transcription. Clin Genet 90:461–465. https://doi.org/10.1111/cge.12756

    Article  CAS  PubMed  Google Scholar 

  • Fischer JC, Ruitenbeek W, Berden JA, Trijbels JM, Veerkamp JH, Stadhouders AM, Sengers RC, Janssen AJ (1985) Differential investigation of the capacity of succinate oxidation in human skeletal muscle. Clin Chim Acta 153:23–36

    Article  CAS  PubMed  Google Scholar 

  • Grings M, Moura AP, Parmeggiani B, Pletsch JT, Cardoso GMF, August PM, Matte C, Wyse ATS, Wajner M, Leipnitz G (2017) Bezafibrate prevents mitochondrial dysfunction, antioxidant system disturbance, glial reactivity and neuronal damage induced by sulfite administration in striatum of rats: implications for a possible therapeutic strategy for sulfite oxidase deficiency. Biochim Biophys Acta 1863:2135–2148. https://doi.org/10.1016/j.bbadis.2017.05.019

    Article  CAS  Google Scholar 

  • Grunert SC, Schlatter SM, Schmitt RN, Gemperle-Britschgi C, Mrazova L, Balci MC, Bischof F, Coker M, Das AM, Demirkol M, de Vries M, Gokcay G, Haberle J, Ucar SK, Lotz-Havla AS, Lucke T, Roland D, Rutsch F, Santer R, Schlune A, Staufner C, Schwab KO, Mitchell GA, Sass JO (2017) 3-hydroxy-3-methylglutaryl-coenzyme a lyase deficiency: clinical presentation and outcome in a series of 37 patients. Mol Genet Metab 121:206–215. https://doi.org/10.1016/j.ymgme.2017.05.014

    Article  CAS  PubMed  Google Scholar 

  • Habig WH, Pabst MJ, Jakoby WB (1974) Glutathione s-transferases. The first enzymatic step in mercapturic acid formation. J Biol Chem 249:7130–7139

    CAS  Google Scholar 

  • Halliwell B, Gutteridge JM (2015) Free radicals in biology and medicine. Oxford University Press, Cary. https://doi.org/10.1093/acprof:oso/9780198717478.001.0001

    Book  Google Scholar 

  • Huang Y, Powers C, Moore V, Schafer C, Ren M, Phoon CK, James JF, Glukhov AV, Javadov S, Vaz FM, Jefferies JL, Strauss AW, Khuchua Z (2017) The PPAR pan-agonist bezafibrate ameliorates cardiomyopathy in a mouse model of Barth syndrome. Orphanet J Rare Dis 12:49. https://doi.org/10.1186/s13023-017-0605-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Iqbal K, Liu F, Gong CX (2016) Tau and neurodegenerative disease: The story so far. Nat Rev Neurol 12:15–27. https://doi.org/10.1038/nrneurol.2015.225

    Article  CAS  Google Scholar 

  • Jembrek MJ, Radovanovic V, Vlainic J, Vukovic L, Hanzic N (2018) Neuroprotective effect of zolpidem against glutamate-induced toxicity is mediated via the pi3k/akt pathway and inhibited by pk11195. Toxicology 406-407:58–69. https://doi.org/10.1016/j.tox.2018.05.014

    Article  CAS  Google Scholar 

  • Karihtala P, Soini Y (2007) Reactive oxygen species and antioxidant mechanisms in human tissues and their relation to malignancies. APMIS 115:81–103. https://doi.org/10.1111/j.1600-0463.2007.apm_514.x

    Article  CAS  PubMed  Google Scholar 

  • Kemper MF, Stirone C, Krause DN, Duckles SP, Procaccio V (2014) Genomic and non-genomic regulation of pgc1 isoforms by estrogen to increase cerebral vascular mitochondrial biogenesis and reactive oxygen species protection. Eur J Pharmacol 723:322–329. https://doi.org/10.1016/j.ejphar.2013.11.009

    Article  CAS  PubMed  Google Scholar 

  • Kim E, Sheng M (2004) Pdz domain proteins of synapses. Nat Rev Neurosci 5:771–781. https://doi.org/10.1038/nrn1517

    Article  CAS  Google Scholar 

  • Kreisler A, Duhamel A, Vanbesien-Mailliot C, Destee A, Bordet R (2010) Differing short-term neuroprotective effects of the fibrates fenofibrate and bezafibrate in mptp and 6-ohda experimental models of Parkinson’s disease. Behav Pharmacol 21:194–205. https://doi.org/10.1097/FBP.0b013e32833a5c81

    Article  CAS  PubMed  Google Scholar 

  • Leipnitz G, Seminotti B, Haubrich J, Dalcin MB, Dalcin KB, Solano A, de Bortoli G, Rosa RB, Amaral AU, Dutra-Filho CS, Latini A, Wajner M (2008) Evidence that 3-hydroxy-3-methylglutaric acid promotes lipid and protein oxidative damage and reduces the nonenzymatic antioxidant defenses in rat cerebral cortex. J Neurosci Res 86:683–693. https://doi.org/10.1002/jnr.21527

    Article  CAS  PubMed  Google Scholar 

  • Leipnitz G, Seminotti B, Fernandes CG, Amaral AU, Beskow AP, da Silva Lde B, Zanatta A, Ribeiro CA, Vargas CR, Wajner M (2009) Striatum is more vulnerable to oxidative damage induced by the metabolites accumulating in 3-hydroxy-3-methylglutaryl-coa lyase deficiency as compared to liver. Int J Dev Neurosci 27:351–356. https://doi.org/10.1016/j.ijdevneu.2009.03.001

    Article  CAS  Google Scholar 

  • Leong SF, Clark JB (1984) Regional development of glutamate dehydrogenase in the rat brain. J Neurochem 43:106–111

    Article  CAS  PubMed  Google Scholar 

  • Li X, Ding Y, Ma Y, Liu Y, Wang Q, Song J, Yang Y (2015) Very long-chain acyl-coenzyme a dehydrogenase deficiency in Chinese patients: eight case reports, including one case of prenatal diagnosis. Eur J Med Genet 58:134–139. https://doi.org/10.1016/j.ejmg.2015.01.005

    Article  PubMed  Google Scholar 

  • Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the folin phenol reagent. J Biol Chem 193:265–275

    CAS  Google Scholar 

  • Mandel H, Saita S, Edvardson S, Jalas C, Shaag A, Goldsher D, Vlodavsky E, Langer T, Elpeleg O (2016) Deficiency of htra2/omi is associated with infantile neurodegeneration and 3-methylglutaconic aciduria. J Med Genet 53:690–696. https://doi.org/10.1136/jmedgenet-2016-103922

    Article  CAS  PubMed  Google Scholar 

  • Noe N, Dillon L, Lellek V, Diaz F, Hida A, Moraes CT, Wenz T (2013) Retracted: Bezafibrate improves mitochondrial function in the CNS of a mouse model of mitochondrial encephalopathy. Mitochondrion 13:417–426. https://doi.org/10.1016/j.mito.2012.12.003

    Article  CAS  PubMed  Google Scholar 

  • Ogier de Baulny H, Saudubray JM (2002) Branched-chain organic acidurias. Semin Neonatol 7:65–74. https://doi.org/10.1053/siny.2001.0087

    Article  CAS  PubMed  Google Scholar 

  • Oguchi T, Ono R, Tsuji M, Shozawa H, Somei M, Inagaki M, Mori Y, Yasumoto T, Ono K, Kiuchi Y (2017) Cilostazol suppresses abeta-induced neurotoxicity in sh-sy5y cells through inhibition of oxidative stress and mapk signaling pathway. Front Aging Neurosci 9:337. https://doi.org/10.3389/fnagi.2017.00337

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Olsen RK, Cornelius N, Gregersen N (2013) Genetic and cellular modifiers of oxidative stress: what can we learn from fatty acid oxidation defects? Mol Genet Metab 110(Suppl):S31–S39. https://doi.org/10.1016/j.ymgme.2013.10.007

    Article  CAS  PubMed  Google Scholar 

  • Ozand PT, al Aqeel A, Gascon G, Brismar J, Thomas E, Gleispach H (1991) 3-hydroxy-3-methylglutaryl-coenzyme a (hmg-coa) lyase deficiency in Saudi Arabia. J Inherit Metab Dis 14:174–188

    Article  CAS  PubMed  Google Scholar 

  • Ribeiro M, Rosenstock TR, Cunha-Oliveira T, Ferreira IL, Oliveira CR, Rego AC (2012) Glutathione redox cycle dysregulation in Huntington’s disease knock-in striatal cells. Free Radic Biol Med 53:1857–1867. https://doi.org/10.1016/j.freeradbiomed.2012.09.004

    Article  CAS  PubMed  Google Scholar 

  • Rokicki D, Pajdowska M, Trubicka J, Thong MK, Ciara E, Piekutowska-Abramczuk D, Pronicki M, Sikora R, Haidar R, Oltarzewski M, Jablonska E, Muthukumarasamy P, Sthaneswar P, Gan CS, Krajewska-Walasek M, Carrozzo R, Verrigni D, Semeraro M, Rizzo C, Taurisano R, Alhaddad B, Kovacs-Nagy R, Haack TB, Dionisi-Vici C, Pronicka E, Wortmann SB (2017) 3-methylglutaconic aciduria, a frequent but underrecognized finding in carbamoyl phosphate synthetase I deficiency. Clin Chim Acta 471:95–100. https://doi.org/10.1016/j.cca.2017.05.023

    Article  CAS  PubMed  Google Scholar 

  • Ruesch S, Krahenbuhl S, Kleinle S, Liechti-Gallati S, Schaffner T, Wermuth B, Weber J, Wiesmann UN, Saudubray JM (1996) Combined 3-methylglutaconic and 3-hydroxy-3-methylglutaric aciduria with endocardial fibroelastosis and dilatative cardiomyopathy in male and female siblings with partial deficiency of complex II/III in fibroblasts. Enzyme Protein 49:321–329

    Article  CAS  PubMed  Google Scholar 

  • Rustin P, Chretien D, Bourgeron T, Gerard B, Rotig A, Saudubray JM, Munnich A (1994) Biochemical and molecular investigations in respiratory chain deficiencies. Clin Chim Acta 228:35–51

    Article  CAS  PubMed  Google Scholar 

  • Saudubray JM, Baumgartner MR, Walter J (2016) Inborn metabolic diseases: diagnosis and treatment. Springer, Berlin

    Book  Google Scholar 

  • Saunders C, Smith L, Wibrand F, Ravn K, Bross P, Thiffault I, Christensen M, Atherton A, Farrow E, Miller N, Kingsmore SF, Ostergaard E (2015) Clpb variants associated with autosomal-recessive mitochondrial disorder with cataract, neutropenia, epilepsy, and methylglutaconic aciduria. Am J Hum Genet 96:258–265. https://doi.org/10.1016/j.ajhg.2014.12.020

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schmitt U, Tanimoto N, Seeliger M, Schaeffel F, Leube RE (2009) Detection of behavioral alterations and learning deficits in mice lacking synaptophysin. Neuroscience 162:234–243. https://doi.org/10.1016/j.neuroscience.2009.04.046

    Article  CAS  PubMed  Google Scholar 

  • Seminotti B, Amaral AU, Ribeiro RT, Rodrigues MDN, Colin-Gonzalez AL, Leipnitz G, Santamaria A, Wajner M (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

    Article  CAS  Google Scholar 

  • Shaerzadeh F, Motamedi F, Khodagholi F (2014) Inhibition of akt phosphorylation diminishes mitochondrial biogenesis regulators, tricarboxylic acid cycle activity and exacerbates recognition memory deficit in rat model of Alzheimer’s disease. Cell Mol Neurobiol 34:1223–1233. https://doi.org/10.1007/s10571-014-0099-9

    Article  CAS  PubMed  Google Scholar 

  • Shahrour MA, Staretz-Chacham O, Dayan D, Stephen J, Weech A, Damseh N, Pri Chen H, Edvardson S, Mazaheri S, Saada A, Sequencing NI, Hershkovitz E, Shaag A, Huizing M, Abu-Libdeh B, Gahl WA, Azem A, Anikster Y, Vilboux T, Elpeleg O, Malicdan MC (2017) Mitochondrial epileptic encephalopathy, 3-methylglutaconic aciduria and variable complex v deficiency associated with timm50 mutations. Clin Genet 91:690–696. https://doi.org/10.1111/cge.12855

    Article  CAS  PubMed  Google Scholar 

  • Shima A, Yasuno T, Yamada K, Yamaguchi M, Kohno R, Yamaguchi S, Kido H, Fukuda H (2016) First Japanese case of carnitine palmitoyltransferase ii deficiency with the homozygous point mutation s113l. Intern Med 55:2659–2661. https://doi.org/10.2169/internalmedicine.55.6288

    Article  PubMed  Google Scholar 

  • Shioya A, Takuma H, Yamaguchi S, Ishii A, Hiroki M, Fukuda T, Sugie H, Shigematsu Y, Tamaoka A (2014) Amelioration of acylcarnitine profile using bezafibrate and riboflavin in a case of adult-onset glutaric acidemia type 2 with novel mutations of the electron transfer flavoprotein dehydrogenase (etfdh) gene. J Neurol Sci 346:350–352. https://doi.org/10.1016/j.jns.2014.08.040

    Article  PubMed  Google Scholar 

  • Singh P, Jain A, Kaur G (2004) Impact of hypoglycemia and diabetes on CNS: correlation of mitochondrial oxidative stress with DNA damage. Mol Cell Biochem 260:153–159

    Article  CAS  PubMed  Google Scholar 

  • Sofer S, Schweiger A, Blumkin L, Yahalom G, Anikster Y, Lev D, Ben-Zeev B, Lerman-Sagie T, Hassin-Baer S (2015) The neuropsychological profile of patients with 3-methylglutaconic aciduria type III, costeff syndrome. Am J Med Genet B Neuropsychiatr Genet 168B:197–203. https://doi.org/10.1002/ajmg.b.32296

    Article  CAS  PubMed  Google Scholar 

  • Srivastava P, Dhuriya YK, Kumar V, Srivastava A, Gupta R, Shukla RK, Yadav RS, Dwivedi HN, Pant AB, Khanna VK (2018) Pi3k/akt/gsk3beta induced creb activation ameliorates arsenic mediated alterations in nmda receptors and associated signaling in rat hippocampus: neuroprotective role of curcumin. Neurotoxicology 67:190–205. https://doi.org/10.1016/j.neuro.2018.04.018

    Article  CAS  PubMed  Google Scholar 

  • Valero T (2014) Mitochondrial biogenesis: pharmacological approaches. Curr Pharm Des 20:5507–5509

    Article  CAS  PubMed  Google Scholar 

  • van der Knaap MS, Bakker HD, Valk J (1998) Mr imaging and proton spectroscopy in 3-hydroxy-3-methylglutaryl coenzyme a lyase deficiency. AJNR Am J Neuroradiol 19:378–382

    PubMed  Google Scholar 

  • Vockley J, Zschocke J, Knerr I, Vockley CW, Michael Gibson K (2014) Branched chain organic acidurias. In: Beaudet AL, Vogelstein B, Kinzler KW, Antonarakis SE, Ballabio A, Gibson KM, Mitchell G (eds) The online metabolic and molecular bases of inherited disease. The McGraw-Hill Companies, Inc., New York http://ommbid.mhmedical.com/content.aspx?bookid=971&sectionid=62676787. Accessed 14 Feb 2019

    Google Scholar 

  • Wendel A (1981) Glutathione peroxidase. In: Methods in enzymology, vol 77. Elsevier, Amsterdam, pp 325–333

    Google Scholar 

  • Wortmann SB, Rodenburg RJ, Jonckheere A, de Vries MC, Huizing M, Heldt K, van den Heuvel LP, Wendel U, Kluijtmans LA, Engelke UF, Wevers RA, Smeitink JA, Morava E (2009) Biochemical and genetic analysis of 3-methylglutaconic aciduria type iv: a diagnostic strategy. Brain 132:136–146. https://doi.org/10.1093/brain/awn296

    Article  PubMed  Google Scholar 

  • Wortmann SB, Kremer BH, Graham A, Willemsen MA, Loupatty FJ, Hogg SL, Engelke UF, Kluijtmans LA, Wanders RJ, Illsinger S, Wilcken B, Cruysberg JR, Das AM, Morava E, Wevers RA (2010) 3-methylglutaconic aciduria type i redefined: a syndrome with late-onset leukoencephalopathy. Neurology 75:1079–1083. https://doi.org/10.1212/WNL.0b013e3181f39a8a

    Article  CAS  PubMed  Google Scholar 

  • Wortmann SB, Kluijtmans LA, Engelke UF, Wevers RA, Morava E (2012) The 3-methylglutaconic acidurias: what’s new? J Inherit Metab Dis 35:13–22. https://doi.org/10.1007/s10545-010-9210-7

    Article  CAS  PubMed  Google Scholar 

  • Wortmann SB, Zietkiewicz S, Kousi M, Szklarczyk R, Haack TB, Gersting SW, Muntau AC, Rakovic A, Renkema GH, Rodenburg RJ, Strom TM, Meitinger T, Rubio-Gozalbo ME, Chrusciel E, Distelmaier F, Golzio C, Jansen JH, van Karnebeek C, Lillquist Y, Lucke T, Ounap K, Zordania R, Yaplito-Lee J, van Bokhoven H, Spelbrink JN, Vaz FM, Pras-Raves M, Ploski R, Pronicka E, Klein C, Willemsen MA, de Brouwer AP, Prokisch H, Katsanis N, Wevers RA (2015) Clpb mutations cause 3-methylglutaconic aciduria, progressive brain atrophy, intellectual disability, congenital neutropenia, cataracts, movement disorder. Am J Hum Genet 96:245–257. https://doi.org/10.1016/j.ajhg.2014.12.013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xu H, He J, Richardson JS, Li XM (2004) The response of synaptophysin and microtubule-associated protein 1 to restraint stress in rat hippocampus and its modulation by venlafaxine. J Neurochem 91:1380–1388. https://doi.org/10.1111/j.1471-4159.2004.02827.x

    Article  CAS  PubMed  Google Scholar 

  • Yagi K (1998) Simple procedure for specific assay of lipid hydroperoxides in serum or plasma. Methods Mol Biol 108:107–110. https://doi.org/10.1385/0-89603-472-0:107

    Article  CAS  PubMed  Google Scholar 

  • Yalcinkaya C, Dincer A, Gunduz E, Ficicioglu C, Kocer N, Aydin A (1999) MRI and MRS in HMG-CoA lyase deficiency. Pediatr Neurol 20:375–380

    Article  CAS  PubMed  Google Scholar 

  • Yamaguchi S, Li H, Purevsuren J, Yamada K, Furui M, Takahashi T, Mushimoto Y, Kobayashi H, Hasegawa Y, Taketani T, Fukao T, Fukuda S (2012) Bezafibrate can be a new treatment option for mitochondrial fatty acid oxidation disorders: evaluation by in vitro probe acylcarnitine assay. Mol Genet Metab 107:87–91. https://doi.org/10.1016/j.ymgme.2012.07.004

    Article  CAS  PubMed  Google Scholar 

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Funding

This work was supported by grants from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) # 409009/2016-4, Programa de Apoio a Núcleos de Excelência (PRONEX II) # 16/2551-0000465-0, Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul (FAPERGS) # 17/2551-0001022-1, Rede Instituto Brasileiro de Neurociência (IBN-Net) # 01.06.0842-00, and Instituto Nacional de Ciência e Tecnologia em Excitotoxicidade e Neuroproteção (INCT-EN) # 465671/2014-4.

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  1. Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, 2600 Ramiro Barcelos Street – Attached, Porto Alegre, Rio Grande do Sul, CEP 90035-003, Brazil

    Nevton Teixeira da Rosa-Junior, Belisa Parmeggiani, Mateus Struecker da Rosa, Nícolas Manzke Glänzel, Leonardo de Moura Alvorcem, Moacir Wajner & Guilhian Leipnitz

  2. Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, 2600 Ramiro Barcelos Street – Attached, Porto Alegre, Rio Grande do Sul, CEP 90035-003, Brazil

    Moacir Wajner & Guilhian Leipnitz

  3. Serviço de Genética Médica, Hospital de Clínicas de Porto Alegre, 2350 Ramiro Barcelos Street, Porto Alegre, Rio Grande do Sul, CEP 90035-903, Brazil

    Moacir Wajner

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  4. Nícolas Manzke Glänzel
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  5. Leonardo de Moura Alvorcem
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  6. Moacir Wajner
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  7. Guilhian Leipnitz
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Corresponding author

Correspondence to Guilhian Leipnitz.

Ethics declarations

The experimental protocol was approved by the Ethics Committee for Animal Research of the Universidade Federal do Rio Grande do Sul, Brazil, and followed the NIH Guide for the Care and Use of Laboratory Animals (NIH publication 85-23, revised in 1985). All efforts were made to minimize the number of animals used and their suffering.

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da Rosa-Junior, N.T., Parmeggiani, B., da Rosa, M.S. et al. Bezafibrate In Vivo Administration Prevents 3-Methylglutaric Acid-Induced Impairment of Redox Status, Mitochondrial Biogenesis, and Neural Injury in Brain of Developing Rats. Neurotox Res 35, 809–822 (2019). https://doi.org/10.1007/s12640-019-00019-9

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