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Drug Res (Stuttg) 2018; 68(05): 263-269
DOI: 10.1055/s-0043-121220
Original Article
© Georg Thieme Verlag KG Stuttgart · New York

Antioxidant and Neuroprotective Effects of KM-34, A Novel Synthetic Catechol, Against Oxidative Stress-Induced Neurotoxicity

Yanier Nuñez-Figueredo
1   Centro de Investigación y Desarrollo de Medicamentos, Ciudad Habana, Cuba
,
Jeney Ramirez-Sanchez
1   Centro de Investigación y Desarrollo de Medicamentos, Ciudad Habana, Cuba
,
Yeniceis Alcantara Issac
1   Centro de Investigación y Desarrollo de Medicamentos, Ciudad Habana, Cuba
,
Estael Ochoa-Rodriguez
2   Laboratorio de Síntesis Orgánica de La Facultad de Química de La Universidad de La Habana Ciudad de la Habana, Cuba
,
Yamila Verdecia-Reyes
2   Laboratorio de Síntesis Orgánica de La Facultad de Química de La Universidad de La Habana Ciudad de la Habana, Cuba
,
Rene Delgado-Hernandez
3   Centro de Estudio para las Investigaciones y Evaluaciones Biológicas, Instituto de Farmacia y Alimentos, Universidad de La Habana, Ciudad Habana, Cuba
,
Diogo O. Souza
4   Departamento de Bioquímica, PPG em Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
,
Gilberto L. Pardo Andreu
3   Centro de Estudio para las Investigaciones y Evaluaciones Biológicas, Instituto de Farmacia y Alimentos, Universidad de La Habana, Ciudad Habana, Cuba
› Author Affiliations
Further Information

Publication History

received 09 August 2017

accepted 05 October 2017

Publication Date:
03 November 2017 (online)

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Abstract

Free radicals are important mediators in a number of neurodegenerative diseases and molecules capable of scavenging reactive oxygen species (ROS) may be a feasible strategy for protecting neuronal cells. In this sense, polyphenols have been studied for their antioxidant effects, KM-34 (5-(3, 4-dydroxyl-benzylidene)-2, 2-dimethyl-1, 3-dioxane-4, 6-Dione) is a novel synthetic catechol with potential neuroprotective and antioxidant properties. We have assessed the antioxidant (as scavenging and iron-chelating compound) and neuroprotectant in vitro (in PC12 cell injury induced by H2O2, glutamate or FeSO4/AA) of KM-34. KM-34 was found to be a potent antioxidant, as shown by (i) inhibition of iron induced-brain lipid peroxidation, (ii) inhibition of 2-deoxyribose degradation, (iii) inhibition of superoxide radicals generation (IC50=11.04 μM) and (iv) inhibition of 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical reduction (IC50=16.26 μM). The overall anti-oxidant action of KM-34 appears to be a combination of a direct reaction with free radicals and chelating the metal ions responsible for the production of ROS. Our work suggests that the antioxidant properties of KM-34 may provide future therapeutic approaches for neurodegenerative disorders.

Key words

KM-34 - 5-(3,4-dydroxyl-benzylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione - antioxidant - neuroprotective drug - PC12
 

  • References

  • 1 Gaspar A, Milhazes N, Santana L. et al. Oxidative stress and neurodegenerative diseases: Looking for a therapeutic solution inspired on benzopyran chemistry. Curr Top Med Chem 2015; 15: 432-445
    CrossrefPubMedGoogle Scholar
  • 2 Kehrer JP, Klotz LO. Free radicals and related reactive species as mediators of tissue injury and disease: Implications for Health. Crit Rev Toxicol 2015; 45: 765-798
    CrossrefPubMedGoogle Scholar
  • 3 Shohami E, Beit-Yannai E, Horowitz M. et al. Oxidative stress in closed-head injury: Brain antioxidant capacity as an indicator of functional outcome. J Cereb Blood Flow Metab 1997; 17: 1007-1019
    CrossrefPubMedGoogle Scholar
  • 4 Molino S, Dossena M, Buonocore D. et al. Polyphenols in dementia: From molecular basis to clinical trials. Life Sci. 2016; 161: 69-77
    CrossrefPubMedGoogle Scholar
  • 5 Simonyi A, Wang Q, Miller RL. et al. Polyphenols in cerebral ischemia: novel targets for neuroprotection. Mol Neurobiol. 2005; 31: 135-147
    CrossrefPubMedGoogle Scholar
  • 6 Lalkovicova M, Danielisova V. Neuroprotection and antioxidants. Neural Regen Res 2016; 11: 865-874
    PubMedGoogle Scholar
  • 7 Ochoa-Rodriguez E, Verdecia-Reyes Y, Nuñez-Figueredo Y et al. Phenolic compound and combination thereof with a benzodiazepine fused to 1,4 dihydropyridine for the treatment of conditions of the central and vascular nervous system. CU Patent 2016-59
    PubMed
  • 8 Genet S, Kale RK, Baquer NZ. Alterations in antioxidant enzymes and oxidative damage in experimental diabetic rat tissues: Effect of vanadate and fenugreek (Trigonellafoenum graecum). Mol Cell Biochem 2002; 236: 7-12
    CrossrefPubMedGoogle Scholar
  • 9 Buege JA, Aust SD. Microsomal lipid peroxidation. Methods Enzymol 1978; 52: 302-310
    CrossrefPubMedGoogle Scholar
  • 10 Figueredo YN, Garcia-Pupo L, Cuesta Rubio O. et al A strong protective action of guttiferone-A, a naturally occurring prenylated benzophenone, against iron-induced neuronal cell damage. J Pharmacol Sci. 2011; 116: 36-46
    CrossrefPubMedGoogle Scholar
  • 11 Ozyurek M, Bektasoglu B, Guclu K. et al. Hydroxyl radical scavenging assay of phenolics and flavonoids with a modified cupric reducing antioxidant capacity (CUPRAC) method using catalase for hydrogen peroxide degradation. Anal Chim Acta. 2008; 616: 196-206
    CrossrefPubMedGoogle Scholar
  • 12 Marklund S, Marklund G. Involvement of the superoxide anion radical in the autoxidation of pyrogallol and a convenient assay for superoxide dismutase. Eur J Biochem. 1974; 47: 469-474
    CrossrefPubMedGoogle Scholar
  • 13 Nunez-Figueredo Y, García-Pupo L, Ramírez-Sánchez J. et al. Neuroprotective action and free radical scavenging activity of Guttiferone-A, a naturally occurring prenylated benzophenone. Arzneimittelforschung 2012; 62: 583-589
    Article in Thieme ConnectPubMedGoogle Scholar
  • 14 Dorta DJ, Pigoso AA, Mingatto FE. et al. Antioxidant activity of flavonoids in isolated mitochondria. Phytother Res 2008; 22: 1213-1218
    CrossrefPubMedGoogle Scholar
  • 15 Nuñez-Figueredo Y, Ramírez-Sánchez J, Delgado-Hernández R. et al. J M-20, a novel benzodiazepine-dihydropyridine hybrid molecule, protects mitochondria and prevents ischemic insult-mediated neural cell death in vitro. Eur J Pharmacol 2014; 726: 57-65
    CrossrefPubMedGoogle Scholar
  • 16 Siddiqui MA, Kashyap MP, Kumar V. et al. Differential protection of pre-, co- and post-treatment of curcumin against hydrogen peroxide in PC12 cells. Hum Exp Toxicol 2011; 30 (03) 192-198
    CrossrefPubMedGoogle Scholar
  • 17 Roth Jr. EF, Gilbert HS. The pyrogallol assay for superoxide dismutase: absence of a glutathione artifact. Anal Biochem 1984; 137: 50-53
    CrossrefPubMedGoogle Scholar
  • 18 Alam MN, Bristi NJ, Rafiquzzaman M. Review on in vivo and in vitro methods evaluation of antioxidant activity. Saudi Pharm J 2013; 21: 143-152
    CrossrefPubMedGoogle Scholar
  • 19 Li L, Du J, Lian Y. et al. Zou L, Wu T. Protective effects of coenzyme Q10 against hydrogen peroxide-induced oxidative stress in PC12 cell: The role of Nrf2 and antioxidant enzymes. Cell Mol Neurobiol 2016; 36: 103-111
    CrossrefPubMedGoogle Scholar
  • 20 Kregel KC, Zhang HJ. An integrated view of oxidative stress in aging: Basic mechanisms, functional effects, and pathological considerations. Am J Physiol Regul Integr Comp Physiol 2007; 292: R18-R36
    CrossrefPubMedGoogle Scholar
  • 21 Bagli E, Goussia A, Moschos MM. et al. Natural compounds and neuroprotection: Mechanisms of action and novel delivery systems. In Vivo 2016; 30: 535-547
    PubMedGoogle Scholar
  • 22 Radak Z, Zhao Z, Goto S. et al. Age-associated neurodegeneration and oxidative damage to lipids, proteins and DNA. Mol Aspects Med 2011; 32: 305-315
    CrossrefPubMedGoogle Scholar
  • 23 Wang X, Michaelis EK. Selective neuronal vulnerability to oxidative stress in the brain. Front Aging Neurosci 2010; 2: 12
    PubMedGoogle Scholar
  • 24 Halliwell B. Oxidative stress and neurodegeneration: Where are we now?. J Neurochem 2006; 97: 1634-1658
    CrossrefPubMedGoogle Scholar
  • 25 Gelain DP, Antonio Behr G, Birnfeld de Oliveira R. et al. Antioxidant therapies for neurodegenerative diseases: Mechanisms, current trends, and perspectives. Oxid Med Cell Longev 2012; 2012: 895153
    PubMedGoogle Scholar
  • 26 Danta CC, Piplani P. The discovery and development of new potential antioxidant agents for the treatment of neurodegenerative diseases. Expert Opin Drug Discov 2014; 9: 1205-1222
    CrossrefPubMedGoogle Scholar
  • 27 Guerra-Araiza C, Álvarez-Mejía AL, Sánchez-Torres S. et al. Effect of natural exogenous antioxidants on aging and on neurodegenerative diseases. Free Radic Res 2013; 47: 451-462
    CrossrefPubMedGoogle Scholar
  • 28 Hiroi M, Ogihara T, Hirano K. et al. Regulation of apoptosis by glutathione redox state in PC12 cells exposed simultaneously to iron and ascorbic acid. Free Radic Biol Med 2005; 38: 1057-1072
    CrossrefPubMedGoogle Scholar
  • 29 Halliwell B. Superoxide-dependent formation of hydroxyl radicals in the presence of iron chelates: Is it a mechanism for hydroxyl radical production in biochemical systems?. FEBS Lett 1978; 92: 321-326
    CrossrefPubMedGoogle Scholar
  • 30 Tadolini B, Cabrini L, Menna C. et al. Iron (III) stimulation of lipid hydroperoxide-dependent lipid peroxidation. Free Radic Res 1997; 27: 563-576
    CrossrefPubMedGoogle Scholar
  • 31 Valgimigli L, Amorati R, Fumo MG. et al. The unusual reaction of semiquinone radicals with molecular oxygen. J Org Chem 2008; 73: 1830-1841
    CrossrefPubMedGoogle Scholar
  • 32 Bendary E, Francis RR, Ali HMG. et al. Antioxidant and structure–activity relationships (SARs) of some phenolic and anilines compounds. Annals of Agricultural Sciences 2013; 58: 173-181
    CrossrefPubMedGoogle Scholar
  • 33 Ordoudi SA, Tsimidou MZ, Vafiadis AP. et al. Structure-DPPH* scavenging activity relationships: Parallel study of catechol and guaiacol acid derivatives. J Agric Food Chem 2006; 54: 5763-5768
    CrossrefPubMedGoogle Scholar
  • 34 Perron NR, Wang HC, Deguire SN. et al. Kinetics of iron oxidation upon polyphenol binding. Dalton Trans 2010; 39: 9982-9987
    CrossrefPubMedGoogle Scholar
  • 35 Silva MM, Santos MR, Caroco G. et al. Structure-antioxidant activity relationships of flavonoids: A re-examination. Free Radic Res 2002; 36: 1219-1227
    CrossrefPubMedGoogle Scholar
  • 36 Kawabata T, Schepkin V, Haramaki N. et al. Iron coordination by catechol derivative antioxidants. Biochem Pharmacol 1996; 51: 1569-1577
    CrossrefPubMedGoogle Scholar
  • 37 Jiang T, Sun Q, Chen S. Oxidative stress: A major pathogenesis and potential therapeutic target of antioxidative agents in Parkinson's disease and Alzheimer's disease. Prog Neurobiol 2016; 147: 1-19
    CrossrefPubMedGoogle Scholar
  • 38 Jomova K, Vondrakova D, Lawson M. et al. Metals, oxidative stress and neurodegenerative disorders. Mol Cell Biochem 2010; 345: 91-104
    CrossrefPubMedGoogle Scholar