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Molecular Neurobiology

, Volume 56, Issue 1, pp 29–38 | Cite as

Bezafibrate Prevents Glycine-Induced Increase of Antioxidant Enzyme Activities in Rat Striatum

  • Belisa Parmeggiani
  • Mateus Grings
  • Nevton Teixeira da Rosa-Junior
  • Renata Britto
  • Moacir Wajner
  • Guilhian LeipnitzEmail author
Article
  • 125 Downloads

Abstract

Non-ketotic hyperglycinemia (NKH) is a severe neurological disorder caused by defects in glycine (GLY) catabolism and characterized by a high cerebrospinal fluid/plasma GLY ratio. Treatment is often ineffective and limited to the control of symptoms and detoxification of GLY. In the present work, we investigated the in vivo effects of GLY intracerebroventricular administration on oxidative stress parameters in rat striatum, cerebral cortex, and hippocampus. In vitro effects of GLY were also evaluated in striatum. The effects of bezafibrate (BEZ), a potential neuroprotective agent, on the possible alterations caused by GLY administration were further evaluated. Our in vivo results showed that GLY increased the activities of the antioxidant enzymes superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione reductase (GR), and glucose-6-phosphate dehydrogenase (G6PDH) in striatum. Furthermore, GLY decreased the concentrations of total glutathione and reduced glutathione (GSH), as well as GSH/oxidized glutathione ratio in vivo in hippocampus. In vitro data also showed that GLY induced lipid peroxidation and decreased GSH in striatum. Regarding the effects of BEZ, we found that GLY-induced increase of GPx, SOD, and GR activities was attenuated or prevented by this compound. However, BEZ did not alter GLY-induced decrease of GSH in hippocampus. We hypothesize that GLY-induced increase of the activities of antioxidant enzymes in striatum occurs as a mechanism to avoid accumulation of reactive oxygen species and consequent oxidative damage. Furthermore, since BEZ prevented GLY-induced alterations, it might be considered as an adjuvant therapy for NKH.

Keywords

Non-ketotic hyperglycinemia Glycine Antioxidant enzymes Bezafibrate Striatum 

Notes

Funding Information

This work was supported by grants from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Programa de Apoio a Núcleos de Excelência (PRONEX II), Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul (FAPERGS), Pró-Reitoria de Pesquisa/Universidade Federal do Rio Grande do Sul (PROPESQ/UFRGS), Financiadora de estudos e projetos (FINEP), Rede Instituto Brasileiro de Neurociência (IBN-Net) # 01.06.0842-00, and Instituto Nacional de Ciência e Tecnologia em Excitotoxicidade e Neuroproteção (INCT-EN).

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Supplementary material

12035_2018_1074_Fig6_ESM.gif (46 kb)
Supplementary figure

Effect of intracerebroventricular administration of glycine (GLY, 5 μmol) on total (GS) (a), reduced (GSH) (b) and oxidized glutathione (GSSG) (c) concentrations, GSH/GSSG ratio (d) and γ-glutamate-cysteine ligase (GCL) activity (e) in rat hippocampus 15 min after the administration. Results are presented as mean ± standard deviation for three to five independent experiments (animals). Statistical analysis was performed using Student’s t test for unpaired samples. *P < 0.05, **P < 0.01, compared to controls. (GIF 45 kb)

12035_2018_1074_MOESM1_ESM.tif (62 kb)
High resolution image (TIF 62 kb)

References

  1. 1.
    Hamosh A, Johnston MV (2001) Non-ketotic hyperglycinemia. In: Scriver CR, Beaudet A, Sly WS, Valle D (eds) The metabolic and molecular bases of inherited disease, vol Editors. 8th edn. McGraw-Hill, New York, pp 2065–2078Google Scholar
  2. 2.
    Applegarth DA, Toone JR (2001) Nonketotic hyperglycinemia (glycine encephalopathy): laboratory diagnosis. Mol Genet Metab 74(1–2):139–146.  https://doi.org/10.1006/mgme.2001.3224 CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Iqbal M, Prasad M, Mordekar SR (2015) Nonketotic hyperglycinemia case series. J Pediatr Neurosci 10(4):355–358.  https://doi.org/10.4103/1817-1745.174445 CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Hoover-Fong JE, Shah S, Van Hove JL, Applegarth D, Toone J, Hamosh A (2004) Natural history of nonketotic hyperglycinemia in 65 patients. Neurology 63(10):1847–1853CrossRefGoogle Scholar
  5. 5.
    Raghavendra S, Ashalatha R, Thomas SV, Kesavadas C (2007) Focal neuronal loss, reversible subcortical focal T2 hypointensity in seizures with a nonketotic hyperglycemic hyperosmolar state. Neuroradiology 49(4):299–305.  https://doi.org/10.1007/s00234-006-0189-6 CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Heindel W, Kugel H, Roth B (1993) Noninvasive detection of increased glycine content by proton MR spectroscopy in the brains of two infants with nonketotic hyperglycinemia. AJNR Am J Neuroradiol 14(3):629–635PubMedPubMedCentralGoogle Scholar
  7. 7.
    Bjoraker KJ, Swanson MA, Coughlin CR 2nd, Christodoulou J, Tan ES, Fergeson M, Dyack S, Ahmad A et al (2016) Neurodevelopmental outcome and treatment efficacy of benzoate and dextromethorphan in siblings with attenuated nonketotic hyperglycinemia. J Pediatr 170:234–239.  https://doi.org/10.1016/j.jpeds.2015.12.027 CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Cusmai R, Martinelli D, Moavero R, Dionisi Vici C, Vigevano F, Castana C, Elia M, Bernabei S et al (2012) Ketogenic diet in early myoclonic encephalopathy due to non ketotic hyperglycinemia. Eur J Paediat Neurol : EJPN : Off J Eur Paediatr Neurol Soc 16(5):509–513.  https://doi.org/10.1016/j.ejpn.2011.12.015 CrossRefGoogle Scholar
  9. 9.
    Zafrir B, Jain M (2014) Lipid-lowering therapies, glucose control and incident diabetes: evidence, mechanisms and clinical implications. Cardiovasc Drugs Ther 28(4):361–377.  https://doi.org/10.1007/s10557-014-6534-9 CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Corona JC, Duchen MR (2015) PPARgamma and PGC-1alpha as therapeutic targets in Parkinson’s. Neurochem Res 40(2):308–316.  https://doi.org/10.1007/s11064-014-1377-0 CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Procaccio V, Bris C, Chao de la Barca JM, Oca F, Chevrollier A, Amati-Bonneau P, Bonneau D, Reynier P (2014) Perspectives of drug-based neuroprotection targeting mitochondria. Rev Neurol 170(5):390–400.  https://doi.org/10.1016/j.neurol.2014.03.005 CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Johri A, Calingasan NY, Hennessey TM, Sharma A, Yang L, Wille E, Chandra A, Beal MF (2012) Pharmacologic activation of mitochondrial biogenesis exerts widespread beneficial effects in a transgenic mouse model of Huntington’s disease. Hum Mol Genet 21(5):1124–1137.  https://doi.org/10.1093/hmg/ddr541 CrossRefPubMedGoogle Scholar
  13. 13.
    Kono Y, Shigetomi E, Inoue K, Kato F (2007) Facilitation of spontaneous glycine release by anoxia potentiates NMDA receptor current in the hypoglossal motor neurons of the rat. Eur J Neurosci 25(6):1748–1756.  https://doi.org/10.1111/j.1460-9568.2007.05426.x CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Moura AP, Grings M, Dos Santos Parmeggiani B, Marcowich GF, Tonin AM, Viegas CM, Zanatta A, Ribeiro CA et al (2013) Glycine intracerebroventricular administration disrupts mitochondrial energy homeostasis in cerebral cortex and striatum of young rats. Neurotox Res 24(4):502–511.  https://doi.org/10.1007/s12640-013-9396-1 CrossRefPubMedGoogle Scholar
  15. 15.
    Moura AP, Parmeggiani B, Grings M, Alvorcem LM, Boldrini RM, Bumbel AP, Motta MM, Seminotti B et al (2015) Intracerebral glycine administration impairs energy and redox homeostasis and induces glial reactivity in cerebral cortex of newborn rats. Mol Neurobiol 53:5864–5875.  https://doi.org/10.1007/s12035-015-9493-7 CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Seminotti B, Knebel LA, Fernandes CG, Amaral AU, da Rosa MS, Eichler P, Leipnitz G, Wajner M (2011) Glycine intrastriatal administration induces lipid and protein oxidative damage and alters the enzymatic antioxidant defenses in rat brain. Life Sci 89 (7–8):276–281. doi: https://doi.org/10.1016/j.lfs.2011.06.013
  17. 17.
    Moura AP, Grings M, Marcowich GF, Bumbel AP, Parmeggiani B, de Moura Alvorcem L, Wajner M, Leipnitz G (2014) Evidence that glycine induces lipid peroxidation and decreases glutathione concentrations in rat cerebellum. Mol Cell Biochem 395(1–2):125–134.  https://doi.org/10.1007/s11010-014-2118-z CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Pai YJ, Leung KY, Savery D, Hutchin T, Prunty H, Heales S, Brosnan ME, Brosnan JT et al (2015) Glycine decarboxylase deficiency causes neural tube defects and features of non-ketotic hyperglycinemia in mice. Nat Commun 6:6388.  https://doi.org/10.1038/ncomms7388 CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Grings M, Moura AP, Parmeggiani B, Pletsch JT, Cardoso GMF, August PM, Matte C, Wyse ATS et al (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(9):2135–2148.  https://doi.org/10.1016/j.bbadis.2017.05.019 CrossRefGoogle Scholar
  20. 20.
    Nakajima T, Tanaka N, Kanbe H, Hara A, Kamijo Y, Zhang X, Gonzalez FJ, Aoyama T (2009) Bezafibrate at clinically relevant doses decreases serum/liver triglycerides via down-regulation of sterol regulatory element-binding protein-1c in mice: a novel peroxisome proliferator-activated receptor alpha-independent mechanism. Mol Pharmacol 75(4):782–792.  https://doi.org/10.1124/mol.108.052928 CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Paxinos G, Watson C (1986) The rat brain in stereotaxic coordinates. Academic Press, San DiegoGoogle Scholar
  22. 22.
    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(2):261–266.  https://doi.org/10.1006/abbi.2001.2292 CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Marklund S, Marklund G (1974) Involvement of the superoxide anion radical in the autoxidation of pyrogallol and a convenient assay for superoxide dismutase. Eur J Biochem 47(3):469–474CrossRefGoogle Scholar
  24. 24.
    Wendel A (1981) Glutathione peroxidase. Methods Enzymol 77:325–333CrossRefGoogle Scholar
  25. 25.
    Carlberg I, Mannervik B (1985) Glutathione reductase. Methods Enzymol 113:484–490CrossRefGoogle Scholar
  26. 26.
    Mannervik B, Guthenberg C (1981) Glutathione transferase (human placenta). Methods Enzymol 77:231–235CrossRefGoogle Scholar
  27. 27.
    Leong SF, Clark JB (1984) Regional enzyme development in rat brain. Enzymes associated with glucose utilization. Biochem J 218(1):131–138CrossRefGoogle Scholar
  28. 28.
    Aebi H (1984) Catalase in vitro. Methods Enzymol 105:121–126CrossRefGoogle Scholar
  29. 29.
    Esterbauer H, Cheeseman KH (1990) Determination of aldehydic lipid peroxidation products: malonaldehyde and 4-hydroxynonenal. Methods Enzymol 186:407–421CrossRefGoogle Scholar
  30. 30.
    Browne RW, Armstrong D (1998) Reduced glutathione and glutathione disulfide. Methods Mol Biol 108:347–352.  https://doi.org/10.1385/0-89603-472-0:347 CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Teare JP, Punchard NA, Powell JJ, Lumb PJ, Mitchell WD, Thompson RP (1993) Automated spectrophotometric method for determining oxidized and reduced glutathione in liver. Clin Chem 39(4):686–689PubMedPubMedCentralGoogle Scholar
  32. 32.
    White CC, Viernes H, Krejsa CM, Botta D, Kavanagh TJ (2003) Fluorescence-based microtiter plate assay for glutamate-cysteine ligase activity. Anal Biochem 318(2):175–180CrossRefGoogle Scholar
  33. 33.
    LeBel CP, Ischiropoulos H, Bondy SC (1992) Evaluation of the probe 2′,7′-dichlorofluorescin as an indicator of reactive oxygen species formation and oxidative stress. Chem Res Toxicol 5(2):227–231CrossRefGoogle Scholar
  34. 34.
    Aksenov MY, Markesbery WR (2001) Changes in thiol content and expression of glutathione redox system genes in the hippocampus and cerebellum in Alzheimer’s disease. Neurosci Lett 302(2–3):141–145CrossRefGoogle Scholar
  35. 35.
    Reznick AZ, Packer L (1994) Oxidative damage to proteins: spectrophotometric method for carbonyl assay. Methods Enzymol 233:357–363CrossRefGoogle Scholar
  36. 36.
    Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193(1):265–275PubMedGoogle Scholar
  37. 37.
    Bannister JV (1986) Free radicals in biology and medicine. Barry Halliwell, John M. C. Gutteridge. Q Rev Biol 61 (3):440–441. doi: https://doi.org/10.1086/415130
  38. 38.
    Kritis AA, Stamoula EG, Paniskaki KA, Vavilis TD (2015) Researching glutamate-induced cytotoxicity in different cell lines: a comparative/collective analysis/study. Front Cell Neurosci 9:91.  https://doi.org/10.3389/fncel.2015.00091 CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Goebel DJ, Poosch MS (1999) NMDA receptor subunit gene expression in the rat brain: a quantitative analysis of endogenous mRNA levels of NR1Com, NR2A, NR2B, NR2C, NR2D and NR3A. Mol Brain Res 69(2):164–170CrossRefGoogle Scholar
  40. 40.
    Chaturvedi RK, Beal MF (2013) Mitochondria targeted therapeutic approaches in Parkinson’s and Huntington’s diseases. Mol Cell Neurosci 55:101–114.  https://doi.org/10.1016/j.mcn.2012.11.011 CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Valero T (2014) Mitochondrial biogenesis: pharmacological approaches. Curr Pharm Des 20(35):5507–5509CrossRefGoogle Scholar
  42. 42.
    Schmitt K, Grimm A, Kazmierczak A, Strosznajder JB, Gotz J, Eckert A (2012) Insights into mitochondrial dysfunction: aging, amyloid-beta, and tau-A deleterious trio. Antioxid Redox Signal 16(12):1456–1466.  https://doi.org/10.1089/ars.2011.4400 CrossRefPubMedPubMedCentralGoogle Scholar

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© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da SaúdeUniversidade Federal do Rio Grande do SulPorto AlegreBrazil
  2. 2.Serviço de Genética Médica do Hospital de Clínicas de Porto AlegrePorto AlegreBrazil
  3. 3.Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Departamento de Bioquímica, Instituto de Ciências Básicas da SaúdeUniversidade Federal do Rio Grande do SulPorto AlegreBrazil

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