Abstract
Methylmalonic acidemia is a genetic disease characterized by accumulation of organic acids, such as methylmalonic (MMA) and malonic (MA) acids. Considering that the accumulation of MMA and MA causes several damages due to oxidative stress, antioxidants are thought to play a pivotal role in preventing deleterious effects associated with exposure to such compounds. Ilex paraguariensis (IP) was used here to test the hypothesis that supplementation with the aqueous extract of this plant could exert protective effect against MMA or MA induced mortality, behavioral and/or biochemical changes in Drosophila melanogaster (DM). Initially, a curve time- and dose–response to MMA (1–10 mM), MA (1–10 mM) and IP (63–500 μM) was performed. Thereafter, flies were concomitantly exposed to MA (5 mM), MMA (5 mM) and/or IP (250 μg/mL) during 15 days for survival assay, and for 48 hs to MA (1 or 5 mM), MMA (1 or 5 mM) and/or IP (250 μg/mL) for subsequent investigations. Both MMA and MA exposure resulted in higher incidence of mortality, a worse performance in the negative geotaxis assay and increased locomotion in open-field test as compared with control group. Furthermore, a marked increase in non-protein thiol (NPSH) and in thiobarbituric acid reactive substances (TBARS) levels, decrease in superoxide dismutase (SOD), catalase and acetylcholinesterase (AChE) activities, and decrease in MTT and resazurin reduction were noted in MMA or MA treated groups. IP treatment offered significant protection against all alterations associated to MMA or MA exposure. This study confirm the hypothesis that supplementation with IP offers protection against changes associated to MMA or MA exposure in DM, due, at least in part, to its antioxidant effect.
Similar content being viewed by others
References
Panigrahi I, Bhunwal S, Varma H, Singh S (2017) Methylmalonic acidemia with novel MUT gene mutations. Case Rep Genet 2017:8984951
Melo DR, Kowaltowski AJ, Wajner M, Castilho RF (2011) Mitochondrial energy metabolism in neurodegeneration associated with methylmalonic acidemia. J Bioenerg Biomembr 43:39–46
Stepien KM, Heaton R, Rankin S, Murphy A, Bentley J, Sexton D, Hargreaves IP (2017) Evidence of oxidative stress and secondary mitochondrial dysfunction in metabolic and non-metabolic disorders. J Clin Med 6:89
Wajner M, Goodman SI (2011) Disruption of mitochondrial homeostasis in organic acidurias: insights from human and animal studies. J Bioenerg Biomembr 43:31–38
Melo DR, Mirandola SR, Assuncao NA, Castilho RF (2012) Methylmalonate impairs mitochondrial respiration supported by NADH-linked substrates: involvement of mitochondrial glutamate metabolism. J Neurosci Res 90:1190–1199
Kolker S, Okun JG (2005) Methylmalonic acid—an endogenous toxin? Cell Mol Life Sci 62:621–624
Kalonia H, Kumar P, Kumar A, Nehru B (2010) Protective effect of montelukast against quinolinic acid/malonic acid induced neurotoxicity: possible behavioral, biochemical, mitochondrial and tumor necrosis factor-alpha level alterations in rats. Neuroscience 171:284–299
Quintanilla RA, Tapia C, Perez MJ (2017) Possible role of mitochondrial permeability transition pore in the pathogenesis of Huntington disease. Biochem Biophys Res Commun 483:1078–1083
Rodrigues CF, Salgueiro W, Bianchini M, Veit JC, Puntel RL, Emanuelli T, Dernadin CC, Avila DS (2018) Salvia hispanica L. (chia) seeds oil extracts reduce lipid accumulation and produce stress resistance in Caenorhabditis elegans. Nutr Metab 15:83
Soares MV, Puntel RL, Avila DS (2018) Resveratrol attenuates iron-induced toxicity in a chronic post-treatment paradigm in Caenorhabditis elegans. Free Radic Res 52:939–951
Portela JL, Soares D, Rosa H, Roos DH, Pinton S, Avila DS, Puntel RL (2017) Ilex paraguariensis crude extract acts on protection and reversion from damage induced by t-butyl hydroperoxide in human erythrocytes: a comparative study with isolated caffeic and/or chlorogenic acids. J Sci Food Agric 97:2007–2014
Bianchini MC, Gularte CO, Escoto DF, Pereira G, Gayer MC, Roehrs R, Soares FA, Puntel RL (2016) Peumus boldus (Boldo) aqueous extract present better protective effect than boldine against manganese-induced toxicity in D. melanogaster. Neurochem Res 41:2699–2707
Courtes AA, Arantes LP, Barcelos RP, da Silva IK, Boligon AA, Athayde ML, Puntel RL, Soares FA (2015) Protective effects of aqueous extract of Luehea divaricata against behavioral and oxidative changes induced by 3-nitropropionic acid in rats. Evid Complement Altern Med 2015:723431
Martins EN, Pessano NT, Leal L, Roos DH, Folmer V, Puntel GO, Rocha JB, Aschner M, Avila DS, Puntel RL (2012) Protective effect of Melissa officinalis aqueous extract against Mn-induced oxidative stress in chronically exposed mice. Brain Res Bull 87:74–79
Colpo AC, Rosa H, Lima ME, Pazzini CE, de Camargo VB, Bassante FE, Puntel R, Avila DS, Mendez A, Folmer V (2016) Yerba mate (Ilex paraguariensis St. Hill.)-based beverages: how successive extraction influences the extract composition and its capacity to chelate iron and scavenge free radicals. Food Chem 209:185–195
Colpo AC, Lima ME, da Rosa HS, Leal AP, Colares CC, Zago AC, Salgueiro ACF, Bertelli PR, Minetto L, Moura S, Mendez ASL, Folmer V (2017) Ilex paraguariensis extracts extend the lifespan of Drosophila melanogaster fed a high-fat diet. Braz J Med Biol Res 51:e6784
Bracesco N, Sanchez AG, Contreras V, Menini T, Gugliucci A (2011) Recent advances on Ilex paraguariensis research: minireview. J Ethnopharmacol 136:378–384
Rand MD (2010) Drosophotoxicology: the growing potential for Drosophila in neurotoxicology. Neurotoxicol Teratol 32:74–83
Hirth F (2010) Drosophila melanogaster in the study of human neurodegeneration. CNS Neurol Disord 9:504–523
Fernandes CEF, Scapinello J, Bohn A, Boligon AA, Athayde ML, Magro JD, Palliga M, Oliveira JV, Tres MV (2017) Phytochemical profile, antioxidant and antimicrobial activity of extracts obtained from erva-mate (Ilex paraguariensis) fruit using compressed propane and supercritical CO2. J Food Sci Technol 54:98–104
Feany MB, Bender WW (2000) A Drosophila model of Parkinson's disease. Nature 404:394–398
Bianchini MC, Gularte COA, Nogara PA, Krum BN, Gayer MC, Bridi JC, Roos DH, Roehrs R, Fachinetto R, Pinton S, Avila DS, Hirth F, Rocha JBT, Puntel RL (2019) Thimerosal inhibits Drosophila melanogaster tyrosine hydroxylase (DmTyrH) leading to changes in dopamine levels and impaired motor behavior: implications for neurotoxicity. Metallomics 11:362–374
Ohkawa H, Ohishi N, Yagi K (1979) Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem 95:351–358
Ellman GL, Courtney KD, Andres V Jr, Feather-Stone RM (1961) A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem Pharmacol 7:88–95
Lushchak VI, Bagnyukova TV, Husak VV, Luzhna LI, Lushchak OV, Storey KB (2005) Hyperoxia results in transient oxidative stress and an adaptive response by antioxidant enzymes in goldfish tissues. Int J Biochem Cell Biol 37:1670–1680
Soares DCS, Portela JLR, Roos DH, Rodrigues NR, Gomes KK, Macedo GE, Posser T, Franco JL, Hassan W, Puntel RL (2018) Treatment with pentylenetetrazole (PTZ) and 4-aminopyridine (4-AP) differently affects survival, locomotor activity, and biochemical markers in Drosophila melanogaster. Mol Cell Biochem 442:129–142
Araujo SM, de Paula MT, Poetini MR, Meichtry L, Bortolotto VC, Zarzecki MS, Jesse CR, Prigol M (2015) Effectiveness of gamma-oryzanol in reducing neuromotor deficits, dopamine depletion and oxidative stress in a Drosophila melanogaster model of Parkinson's disease induced by rotenone. Neurotoxicology 51:96–105
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
Gabbi P, Ribeiro LR, Jessie Martins G, Cardoso AS, Haupental F, Rodrigues FS, Machado AK, Sperotto Brum J, Medeiros Frescura Duarte MM, Schetinger MR, da Cruz IB, Flavia Furian A, Oliveira MS, Dos Santos AR, Royes LF, Fighera MR, de Freitas ML (2017) Methylmalonate induces inflammatory and apoptotic potential: a link to glial activation and neurological dysfunction. J Neuropathol Exp Neurol 76:160–178
Valdeolivas S, Pazos MR, Bisogno T, Piscitelli F, Iannotti FA, Allara M, Sagredo O, Di Marzo V, Fernandez-Ruiz J (2013) The inhibition of 2-arachidonoyl-glycerol (2-AG) biosynthesis, rather than enhancing striatal damage, protects striatal neurons from malonate-induced death: a potential role of cyclooxygenase-2-dependent metabolism of 2-AG. Cell Death Dis 4:e862
Martin JR (2004) A portrait of locomotor behaviour in Drosophila determined by a video-tracking paradigm. Behav Proc 67:207–219
Hou J, Kuromi H, Fukasawa Y, Ueno K, Sakai T, Kidokoro Y (2004) Repetitive exposures to nicotine induce a hyper-responsiveness via the cAMP/PKA/CREB signal pathway in Drosophila. J Neurobiol 60:249–261
Ren J, Sun J, Zhang Y, Liu T, Ren Q, Li Y, Guo A (2012) Down-regulation of Decapping Protein 2 mediates chronic nicotine exposure-induced locomotor hyperactivity in Drosophila. PLoS ONE 7:e52521
Bainton RJ, Tsai LT, Singh CM, Moore MS, Neckameyer WS, Heberlein U (2000) Dopamine modulates acute responses to cocaine, nicotine and ethanol in Drosophila. Curr Biol 10:187–194
Zhang Y, Guo J, Guo A, Li Y (2016) Nicotine-induced acute hyperactivity is mediated by dopaminergic system in a sexually dimorphic manner. Neuroscience 332:149–159
Niraula P, Ghimire S, Lee H, Kim MS (2018) Ilex paraguariensis Extends lifespan and increases an ability to resist environmental stresses in Drosophila. Rejuvenation Res 21:497–505
Lima ME, Colpo AC, Salgueiro WG, Sardinha GE, Avila DS, Folmer V (2014) Ilex paraguariensis extract increases lifespan and protects against the toxic effects caused by paraquat in Caenorhabditis elegans. Int J Environ Res Public Health 11:10091–10104
Jimenez-Del-Rio M, Guzman-Martinez C, Velez-Pardo C (2010) The effects of polyphenols on survival and locomotor activity in Drosophila melanogaster exposed to iron and paraquat. Neurochem Res 35:227–238
Milioli EM, Cologni P, Santos CC, Marcos TD, Yunes VM, Fernandes MS, Schoenfelder T, Costa-Campos L (2007) Effect of acute administration of hydroalcohol extract of Ilex paraguariensis St Hilaire (Aquifoliaceae) in animal models of Parkinson's disease. Phytother Res 21:771–776
Branco Cdos S, Scola G, Rodrigues AD, Cesio V, Laprovitera M, Heinzen H, Dos Santos MT, Fank B, de Freitas SC, Coitinho AS, Salvador M (2013) Anticonvulsant, neuroprotective and behavioral effects of organic and conventional yerba mate (Ilex paraguariensis St. Hil.) on pentylenetetrazol-induced seizures in Wistar rats. Brain Res Bull 92:60–68
Fu X, Gao X, Ge L, Cui X, Su C, Yang W, Sun X, Zhang W, Yao Z, Yang X, Yang J (2016) Malonate induces the assembly of cytoplasmic stress granules. FEBS Lett 590:22–33
Royes LF, Fighera MR, Furian AF, Oliveira MS, Myskiw Jde C, Fiorenza NG, Petry JC, Coelho RC, Mello CF (2006) Effectiveness of creatine monohydrate on seizures and oxidative damage induced by methylmalonate. Pharmacol Biochem Behav 83:136–144
Connop BP, Boegman RJ, Beninger RJ, Jhamandas K (1997) Malonate-induced degeneration of basal forebrain cholinergic neurons: attenuation by lamotrigine, MK-801, and 7-nitroindazole. J Neurochem 68:1191–1199
Affonso AC, Machado DG, Malgarin F, Fraga DB, Ghedim F, Zugno A, Streck EL, Schuck PF, Ferreira GC (2013) Increased susceptibility of brain acetylcholinesterase activity to methylmalonate in young rats with renal failure. Metab Brain Dis 28:493–500
Tsai TH, Yu CH, Chang YP, Lin YT, Huang CJ, Kuo YH, Tsai PJ (2017) Protective effect of caffeic acid derivatives on tert-butyl hydroperoxide-induced oxidative hepato-toxicity and mitochondrial dysfunction in HepG2 cells. Molecules 22:702
Acknowledgements
This study was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior – Brasil (CAPES) – Finance Code 001. The authors are also grateful to FAPERGS, CNPq, FINEP, INCT-EN and UNIPAMPA. Additional support was given by CNPq/FAPERGS/DECIT/SCTIE-MS/PRONEM #16/2551-0000248-7, CNPq (Universal) research grant #449428/2014-1 and CNPq scholarship (#301807/2018-3).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that there is no conflict of interest.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Portela, J.L., Bianchini, M.C., Boligon, A.A. et al. Ilex paraguariensis Attenuates Changes in Mortality, Behavioral and Biochemical Parameters Associated to Methyl Malonate or Malonate Exposure in Drosophila melanogaster. Neurochem Res 44, 2202–2214 (2019). https://doi.org/10.1007/s11064-019-02862-w
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11064-019-02862-w