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Neurotoxicity Research

, Volume 36, Issue 2, pp 279–291 | Cite as

KM-34, a Novel Antioxidant Compound, Protects against 6-Hydroxydopamine-Induced Mitochondrial Damage and Neurotoxicity

  • Luis Arturo Fonseca-Fonseca
  • Yanier Nuñez-Figueredo
  • Jeney Ramírez Sánchez
  • Maylin Wong Guerra
  • Estael Ochoa-Rodríguez
  • Yamila Verdecia-Reyes
  • René Delgado Hernádez
  • Noelio J. Menezes-Filho
  • Teresa Cristina Silva Costa
  • Wagno Alcântara de Santana
  • Joana L. Oliveira
  • Juan Segura-Aguilar
  • Victor Diogenes Amaral da Silva
  • Silva Lima CostaEmail author
ORIGINAL ARTICLE

Abstract

The etiology of Parkinson’s disease is not completely understood and is believed to be multifactorial. Neuronal disorders associated to oxidative stress and mitochondrial dysfunction are widely considered major consequences. The aim of this study was to investigate the effect of the synthetic arylidenmalonate derivative 5-(3,4-dihydroxybenzylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (KM-34), in oxidative stress and mitochondrial dysfunction induced by 6-hydroxydopamine (6-OHDA). Pretreatment (2 h) with KM-34 (1 and 10 μM) markedly attenuated 6-OHDA-induced PC12 cell death in a concentration-dependent manner. KM-34 also inhibited H2O2 generation, mitochondrial swelling, and membrane potential dissipation after 6-OHDA-induced mitochondrial damage. In vivo, KM-34 treatment (1 and 2 mg/Kg) reduced percentage of asymmetry (cylinder test) and increased the vertical exploration (open field) with respect to untreated injured animals; KM-34 also reduced glial fibrillary acidic protein overexpression and increased tyrosine hydroxylase-positive cell number, both in substantia nigra pars compacta. These results demonstrate that KM-34 present biological effects associated to mitoprotection and neuroprotection in vitro, moreover, glial response and neuroprotection in SNpc in vivo. We suggest that KM-34 could be a putative neuroprotective agent for inhibiting the progressive neurodegenerative disease associated to oxidative stress and mitochondrial dysfunction.

Keywords

KM-34 Arylidenmalonate derived Mitochondria Neuroprotection Parkinson’s disease 

Notes

Acknowledgments

This work was partially supported by CAPES/MES (Brazil-Cuba) project 178/12 2, titled: “Estudo de compostos derivados de arilidenmalonatos e de benzodiazepinas em modelos experimentais de enfermidade de Parkinson, com énfase nos mecanismos neuroinflamatórios, mitocondriais, antioxidantes e apoptótico” and by CAPES/MES (Brazil-Cuba) Project 09-061 “Sistemas heterocíclicos policondensados com potencial atividade antiparasitaria: leishmania e malaria.” Ochoa-Rodriguez E. is indebted to both CAPES/MES projects for contributing to Brazil-Cuba scientific cooperation and particularly for partially funding the synthesis and biological evaluations of different synthetic compounds.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no competing interests.

References

  1. Allbutt HN, Henderson JM (2007) Use of the narrow beam test in the rat, 6-hydroxydopamine model of Parkinson’s disease. J Neurosci Methods 159(2):195–202.  https://doi.org/10.1016/j.jneumeth.2006.07.006 Google Scholar
  2. Berridge MV, Tan AS (1993) Characterization of the cellular reduction of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT): subcellular localization, substrate dependence, and involvement of mitochondrial electron transport in MTT reduction. Arch Biochem Biophys 303(2):474–482.  https://doi.org/10.1006/abbi.1993.1311 Google Scholar
  3. Blesa J, Przedborski S (2014) Parkinson’s disease: animal models and dopaminergic cell vulnerability. Front Neuroanat 8:155.  https://doi.org/10.3389/fnana.2014.00155 Google Scholar
  4. Braak H, Ghebremedhin E, Rüb U, Bratzke H, Tredici KD (2004) Stages in the development of Parkinson’s disease-related pathology. Cell Tissue Res 318(1):121–134.  https://doi.org/10.1007/s00441-004-0956-9 Google Scholar
  5. BureŠ JAN, BureŠOvÁ O, Huston JP (1976) Chapter 2 - INNATE AND MOTIVATED BEHAVIOR. In: Techniques and Basic Experiments for the Study of Brain and Behavior. Elsevier, pp 37–89.  https://doi.org/10.1016/B978-0-444-41502-8.50006-5
  6. Büttner-Ennever J (1997) The rat brain in stereotaxic coordinates, 3rd edn. By George Paxinos and Charles Watson. J Anat 191(2):315–317.  https://doi.org/10.1046/j.1469-7580.1997.191203153.x Google Scholar
  7. Cassarino DS, Parks JK, Parker WD Jr, Bennett JP Jr (1999) The parkinsonian neurotoxin MPP+ opens the mitochondrial permeability transition pore and releases cytochrome c in isolated mitochondria via an oxidative mechanism. Biochim Biophys Acta 1453(1):49–62.  https://doi.org/10.1016/S0925-4439(98)00083-0 Google Scholar
  8. Chan H, Paur H, Vernon AC, Zabarsky V, Datla KP, Croucher MJ, Dexter DT (2010) Neuroprotection and functional recovery associated with decreased microglial activation following selective activation of mGluR2/3 receptors in a rodent model of Parkinson’s disease. Parkinson’s disease 2010:1–12.  https://doi.org/10.4061/2010/190450 Google Scholar
  9. Cheng H, Ulane CM, Burke RE (2010) Clinical progression in Parkinson’s disease and the neurobiology of axons. Ann Neurol 67(6):715–725.  https://doi.org/10.1002/ana.21995 Google Scholar
  10. Dawson TM, Dawson VL (2017) Mitochondrial mechanisms of neuronal cell death: potential therapeutics. Annu Rev Pharmacol Toxicol 57(1):437–454.  https://doi.org/10.1146/annurev-pharmtox-010716-105001 Google Scholar
  11. De Jesus-Cortes H et al (2015) Protective efficacy of P7C3-S243 in the 6-hydroxydopamine model of Parkinson’s disease. NPJ Parkinson’s disease 1(1):889–894.  https://doi.org/10.1038/npjparkd.2015.10 Google Scholar
  12. Decressac M, Mattsson B, Bjorklund A (2012) Comparison of the behavioural and histological characteristics of the 6-OHDA and alpha-synuclein rat models of Parkinson’s disease. Exp Neurol 235(1):306–315.  https://doi.org/10.1016/j.expneurol.2012.02.012 Google Scholar
  13. Duty S, Jenner P (2011) Animal models of Parkinson’s disease: a source of novel treatments and clues to the cause of the disease. Br J Pharmacol 164(4):1357–1391.  https://doi.org/10.1111/j.1476-5381.2011.01426.x Google Scholar
  14. East DA, Campanella M (2016) Mitophagy and the therapeutic clearance of damaged mitochondria for neuroprotection. Int J Biochem Cell Biol 79:382–387.  https://doi.org/10.1016/j.biocel.2016.08.019 Google Scholar
  15. Exner N, Lutz AK, Haass C, Winklhofer KF (2012) Mitochondrial dysfunction in Parkinson’s disease: molecular mechanisms and pathophysiological consequences. EMBO J 31(14):3038–3062.  https://doi.org/10.1038/emboj.2012.170 Google Scholar
  16. Glass CK, Saijo K, Winner B, Marchetto MC, Gage FH (2010) Mechanisms underlying inflammation in neurodegeneration. Cell 140(6):918–934.  https://doi.org/10.1016/j.cell.2010.02.016 Google Scholar
  17. Glinka YY, Youdim MB (1995) Inhibition of mitochondrial complexes I and IV by 6-hydroxydopamine. Eur J Pharmacol 292(3-4):329–332.  https://doi.org/10.1016/0926-6917(95)90040-3 Google Scholar
  18. Golembiowska K, Wardas J, Noworyta-Sokolowska K, Kaminska K, Gorska A (2013) Effects of adenosine receptor antagonists on the in vivo LPS-induced inflammation model of Parkinson’s disease. Neurotox Res 24(1):29–40.  https://doi.org/10.1007/s12640-012-9372-1 Google Scholar
  19. Greenamyre JT, Cannon JR, Drolet R, Mastroberardino PG (2010) Lessons from the rotenone model of Parkinson’s disease. Trends Pharmacol Sci 31(4):141–143.  https://doi.org/10.1016/j.tips.2009.12.006 Google Scholar
  20. Hasegawa K, Yasuda T, Shiraishi C, Fujiwara K, Przedborski S, Mochizuki H (2016) Promotion of mitochondrial biogenesis by necdin protects neurons against mitochondrial insults. Nat Commun 7:10943.  https://doi.org/10.1038/ncomms10943 Google Scholar
  21. Hirsch EC (2009) Iron transport in Parkinson’s disease. Parkinsonism Relat Disord 15(Suppl 3):S209–S211.  https://doi.org/10.1016/s1353-8020(09)70816-8 Google Scholar
  22. Hou L, Xiong N, Liu L, Huang J, Han C, Zhang G, Li J, Xu X, Lin Z, Wang T (2015) Lithium protects dopaminergic cells from rotenone toxicity via autophagy enhancement. BMC Neurosci 16(1):82.  https://doi.org/10.1186/s12868-015-0222-y Google Scholar
  23. Hughes AJ, Daniel SE, Kilford L, Lees AJ (1992) Accuracy of clinical diagnosis of idiopathic study of 100 cases. J Neurol Neurosurg Psychiatry 55(3):181–184.  https://doi.org/10.1136/jnnp.55.3.181 Google Scholar
  24. Jenner P (2003) The contribution of the MPTP-treated primate model to the development of new treatment strategies for Parkinson’s disease. Parkinsonism Relat Disord 9(3):131–137.  https://doi.org/10.1016/s1353-8020(02)00115-3 Google Scholar
  25. Johri A, Beal MF (2012) Mitochondrial dysfunction in neurodegenerative diseases. J Pharmacol Exp Ther 342(3):619–630.  https://doi.org/10.1124/jpet.112.192138 Google Scholar
  26. Kasture S, Pontis S, Pinna A, Schintu N, Spina L, Longoni R, Simola N, Ballero M, Morelli M (2009) Assessment of symptomatic and neuroprotective efficacy of Mucuna pruriens seed extract in rodent model of Parkinson’s disease. Neurotox Res 15(2):111–122.  https://doi.org/10.1007/s12640-009-9011-7 Google Scholar
  27. Kim HDK, Jeong HK, Jung UJ, Kim SR (2016) Myricitrin ameliorates 6-Hydroxydopamine-induced dopaminergic neuronal loss in the substantia Nigra of mouse brain. J Med Food 19(4):1–9.  https://doi.org/10.1089/jmf.2015.3581 Google Scholar
  28. Langston JW, Ballard P, Tetrud JW, Irwin I (1983) Chronic parkinsonism in humans due to a product of meperidine-analog synthesis. Science (New York, NY) 219:979–980. doi: https://doi.org/10.1126/science.6823561, 4587
  29. Liu W, Vives-Bauza C, Acín-Peréz- R, Yamamoto A, Tan Y, Li Y, Magrané J, Stavarache MA, Shaffer S, Chang S, Kaplitt MG, Huang XY, Beal MF, Manfredi G, Li C (2009) PINK1 defect causes mitochondrial dysfunction, proteasomal deficit and alpha-synuclein aggregation in cell culture models of Parkinson’s disease. PLoS One 4(2):e4597.  https://doi.org/10.1371/journal.pone.0004597 Google Scholar
  30. Lotharius J, Dugan LL, O'Malley KL (1999) Distinct mechanisms underlie neurotoxin-mediated cell death in cultured dopaminergic neurons. The Journal of neuroscience : the official journal of the Society for Neuroscience 19(4):1284–1293Google Scholar
  31. Marti M, Trapella C, Viaro R, Morari M (2007) The Nociceptin/Orphanin FQ receptor antagonist J-113397 and L-DOPA additively attenuate experimental parkinsonism through overinhibition of the nigrothalamic pathway. J Neurosci 27(6):1297–1307.  https://doi.org/10.1523/jneurosci.4346-06.2007 Google Scholar
  32. Martin LJ, Pan Y, Price AC, Sterling W, Copeland NG, Jenkins NA, Price DL, Lee MK (2006) Parkinson’s disease alpha-synuclein transgenic mice develop neuronal mitochondrial degeneration and cell death. The Journal of neuroscience : the official journal of the Society for Neuroscience 26(1):41–50.  https://doi.org/10.1523/jneurosci.4308-05.2006 Google Scholar
  33. Mirandola SR, Melo DR, Saito A, Castilho RF (2010) 3-nitropropionic acid-induced mitochondrial permeability transition: comparative study of mitochondria from different tissues and brain regions. J Neurosci Res 88:630–639.  https://doi.org/10.1002/jnr.22239 Google Scholar
  34. Mosmann T (1983) Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 65(1-2):55–63.  https://doi.org/10.1016/0022-1759(83)90303-4 Google Scholar
  35. Murphy MP (2008) Targeting lipophilic cations to mitochondria. Biochim Biophys Acta 1777(7-8):1028–1031.  https://doi.org/10.1016/j.bbabio.2008.03.029 Google Scholar
  36. Nunez-Figueredo Y et al (2014) Antioxidant effects of JM-20 on rat brain mitochondria and synaptosomes: mitoprotection against ca(2) (+)-induced mitochondrial impairment. Brain Res Bull 109:68–76.  https://doi.org/10.1016/j.brainresbull.2014.10.001 Google Scholar
  37. Nunez-Figueredo Y et al (2016) Therapeutic potential of the novel hybrid molecule JM-20 against focal cortical ischemia in rats. Journal of Pharmacy and Pharmacognosy Research 4:153–158Google Scholar
  38. Nuñez-Figueredo Y, Ramirez-Sanchez J, Issac YA, Ochoa-Rodriguez E, Verdecia-Reyes Y, Delgado-Hernandez R, Souza DO, Andreu GLP (2017) Antioxidant and Neuroprotective Effects of KM-34, A Novel Synthetic Catechol, Against Oxidative Stress-Induced Neurotoxicity. Drug Res (Stuttg) 1: 5-60.  https://doi.org/10.1055/s-0043-121220
  39. Palacino JJ, Sagi D, Goldberg MS, Krauss S, Motz C, Wacker M, Klose J, Shen J (2004) Mitochondrial dysfunction and oxidative damage in parkin-deficient mice. J Biol Chem 279(18):18614–18622.  https://doi.org/10.1074/jbc.M401135200 Google Scholar
  40. Pardo-Andreu GL, Nuñez-Figueredo Y, Tudella VG, Cuesta-Rubio O, Rodrigues FP, Pestana CR, Uyemura SA, Leopoldino AM, Alberici LC, Curti C (2011) The anti-cancer agent guttiferone-a permeabilizes mitochondrial membrane: ensuing energetic and oxidative stress implications. Toxicol Appl Pharmacol 253(3):282–289.  https://doi.org/10.1016/j.taap.2011.04.011 Google Scholar
  41. Pavon-Fuentes N et al (2004) Stromal cell transplant in the 6-OHDA lesion model. Rev Neurol 39(4):326–334Google Scholar
  42. Pekny M, Wilhelmsson U, Pekna M (2014) The dual role of astrocyte activation and reactive gliosis. Neurosci Lett 565:30–38.  https://doi.org/10.1016/j.neulet.2013.12.071 Google Scholar
  43. Perier C, Vila M (2012) Mitochondrial biology and Parkinson’s disease. Cold Spring Harbor perspectives in medicine 2(2):a009332.  https://doi.org/10.1101/cshperspect.a009332 Google Scholar
  44. Rauch F, Schwabe K, Krauss JK (2010) Effect of deep brain stimulation in the pedunculopontine nucleus on motor function in the rat 6-hydroxydopamine Parkinson model. Behav Brain Res 210(1):46–53.  https://doi.org/10.1016/j.bbr.2010.02.003 Google Scholar
  45. Redman PT, Jefferson BS, Ziegler CB, Mortensen OV, Torres GE, Levitan ES, Aizenman E (2006) A vital role for voltage-dependent potassium channels in dopamine transporter-mediated 6-hydroxydopamine neurotoxicity. Neuroscience 143(1):1–6.  https://doi.org/10.1016/j.neuroscience.2006.08.039 Google Scholar
  46. Rodriguez-Pallares J, Parga JA, Joglar B, Guerra MJ, Labandeira-Garcia JL (2009) The mitochondrial ATP-sensitive potassium channel blocker 5-hydroxydecanoate inhibits toxicity of 6-hydroxydopamine on dopaminergic neurons. Neurotox Res 15(1):82–95.  https://doi.org/10.1007/s12640-009-9010-8 Google Scholar
  47. Ross GW, Petrovitch H, Abbott RD, Nelson J, Markesbery W, Davis D, Hardman J, Launer L, Masaki K, Tanner CM, White LR (2004) Parkinsonian signs and substantia nigra neuron density in decendents elders without PD. Ann Neurol 56(4):532–539.  https://doi.org/10.1002/ana.20226 Google Scholar
  48. Rugarli EI, Langer T (2012) Mitochondrial quality control: a matter of life and death for neurons. EMBO J 31(6):1336–1349.  https://doi.org/10.1038/emboj.2012.38 Google Scholar
  49. Schallert T, Fleming SM, Leasure JL, Tillerson JL, Bland ST (2000) CNS plasticity and assessment of forelimb sensorimotor outcome in unilateral rat models of stroke, cortical ablation, parkinsonism and spinal cord injury. Neuropharmacology 39(5):777–787.  https://doi.org/10.1016/s0028-3908(00)00005-8 Google Scholar
  50. Schober A (2004) Classic toxin-induced animal models of Parkinson’s disease: 6-OHDA and MPTP. Cell Tissue Res 318(1):215–224.  https://doi.org/10.1007/s00441-004-0938-y Google Scholar
  51. Shearman MS, Hawtin SR, Tailor VJ (1995) The intracellular component of cellular 3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium bromide (MTT) reduction is specifically inhibited by β-amyloid peptides. J Neurochem 65(1):218–227.  https://doi.org/10.1046/j.1471-4159.1995.65010218.x Google Scholar
  52. Stromberg I, Bjorklund H, Dahl D, Jonsson G, Sundstrom E, Olson L (1986) Astrocyte responses to dopaminergic denervations by 6-hydroxydopamine and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine as evidenced by glial fibrillary acidic protein immunohistochemistry. Brain Res Bull 17(2):225–236.  https://doi.org/10.1016/0361-9230(86)90119-X Google Scholar
  53. Sveinbjornsdottir SJ (2016) The clinical symptoms of Parkinson’s disease. Neurochem Suppl 1:318–324.  https://doi.org/10.1111/jnc.13691 Google Scholar
  54. Tanaka K, Ogawa N, Asanuma M (2006) Molecular basis of 6-hydroxydopamine-induced caspase activations due to increases in oxidative stress in the mouse striatum. Neurosci Lett 410(2):85–89.  https://doi.org/10.1016/j.neulet.2006.08.021 Google Scholar
  55. Taylor JM, Main BS, Crack PJ (2013) Neuroinflammation and oxidative stress: co-conspirators in the pathology of Parkinson’s disease. Neurochem Int 62(5):803–819.  https://doi.org/10.1016/j.neuint.2012.12.016 Google Scholar
  56. Ungerstedt U (1968) 6-Hydroxy-dopamine induced degeneration of central monoamine neurons. Eur J Pharmacol 5(1):107–110.  https://doi.org/10.1016/0014-2999(68)90164-7 Google Scholar
  57. Zsurka G, Kunz WS (2013) Mitochondrial involvement in neurodegenerative diseases. IUBMB Life 65(3):263–272.  https://doi.org/10.1002/iub.1126 Google Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2017

Authors and Affiliations

  • Luis Arturo Fonseca-Fonseca
    • 1
  • Yanier Nuñez-Figueredo
    • 1
  • Jeney Ramírez Sánchez
    • 1
  • Maylin Wong Guerra
    • 1
  • Estael Ochoa-Rodríguez
    • 2
  • Yamila Verdecia-Reyes
    • 2
  • René Delgado Hernádez
    • 1
  • Noelio J. Menezes-Filho
    • 3
  • Teresa Cristina Silva Costa
    • 3
  • Wagno Alcântara de Santana
    • 3
  • Joana L. Oliveira
    • 3
  • Juan Segura-Aguilar
    • 4
  • Victor Diogenes Amaral da Silva
    • 3
  • Silva Lima Costa
    • 3
    Email author
  1. 1.Centro de Investigación y Desarrollo de MedicamentosCiudad de la HabanaCuba
  2. 2.Laboratorio de Síntesis Orgánica. Departamento de Química Orgánica. Facultad de QuímicaUniversidad de La Habana (Zapata s/n entre G y Carlitos AguirreCiudad de la HabanaCuba
  3. 3.Laboratório de Neuroquímica e Biologia Celular, Instituto de Ciências da SaúdeUniversidade Federal da Bahia – UFBASalvadorBrazil
  4. 4.Molecular & Clinical Pharmacology, ICBM, Faculty of MedicineUniversity of ChileSantiagoChile

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