Skip to main content

Advertisement

SpringerLink
Log in

3-Pyridinylboronic Acid Ameliorates Rotenone-Induced Oxidative Stress Through Nrf2 Target Genes in Zebrafish Embryos

  • Original Paper
  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

Parkinson’s disease (PD) is one of the most common forms of neurodegenerative diseases and research on potential therapeutic agents for PD continues. Rotenone is a neurotoxin that can pass the blood–brain barrier and is used to generate PD models in experimental animals. Boron is a microelement necessary for neural activity in the brain. Antioxidant, non-cytotoxic, anti-genotoxic, anti-carcinogenic effects of boric acid, the salt compound of boron has been reported before. Boronic acids have been approved for treatment by FDA and are included in drug discovery studies and pyridine boronic acids are a subclass of heterocyclic boronic acids used in drug design and discovery as substituted pyridines based on crystal engineering principles. The aim of our study was to determine the effect of 3-pyridinylboronic acid in rotenone-exposed zebrafish embryos, focusing on oxidant-antioxidant parameters and gene expression levels of nuclear factor erythroid 2-related factor 2 (Nrf2) target genes gclm, gclc, hmox1a, nqo1, and PD related genes, brain-derived neurotrophic factor, dj1, and tnfα. Zebrafish embryos were exposed to Rotenone (10 μg/l); Low Dose 3-Pyridinylboronic acid (100 μM); High Dose 3-Pyridinylboronic acid (200 μM); Rotenone + Low Dose-3-Pyridinylboronic acid (10 μg/l + 100 μM); Rotenone + High Dose-3-Pyridinylboronic acid (10 μg/l + 200 μM) in well plates for 96 h post-fertilization (hpf). Our study showed for the first time that 3-pyridinylboronic acid, as a novel sub-class of the heterocyclic boronic acid compound, improved locomotor activities, ameliorated oxidant-antioxidant status by decreasing LPO and NO levels, and normalized the expressions of bdnf, dj1, tnf⍺ and Nrf2 target genes hmox1a and nqo1 in rotenone exposed zebrafish embryos. On the other hand, it caused the deterioration of the oxidant-antioxidant balance in the control group through increased lipid peroxidation, nitric oxide levels, and decreased antioxidant enzymes. We believe that these results should be interpreted in the context of the dose-toxicity and benefit-harm relationship of the effects of 3-pyridinylboronic.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Data Availability

Data will be available on reasonable request.

References

  1. Üstündaǧ A, Behm C, Föllmann W, Duydu Y, Degen GH (2014) Protective effect of boric acid on lead- and cadmium-induced genotoxicity in V79 cells. Arch Toxicol 88:1281–1289. https://doi.org/10.1007/s00204-014-1235-5

    Article  CAS  PubMed  Google Scholar 

  2. Herrero M, Ibáñez E, Cifuentes A (2005) Analysis of natural antioxidants by capillary electromigration methods. J Sep Sci 28:883–897. https://doi.org/10.1002/jssc.200400104

    Article  CAS  PubMed  Google Scholar 

  3. Türkez H, Geyikoğlu F, Tatar A, Keleş S, Özkan A (2007) Effects of some boron compounds on peripheral human blood. Z Naturforsch C J Biosci 62:889–896. https://doi.org/10.1016/j.etp.2010.06.011

    Article  CAS  PubMed  Google Scholar 

  4. Turkez H (2008) Effects of boric acid and borax on titanium dioxide genotoxicity. J Appl Toxicol 28:658–664. https://doi.org/10.1002/jat.1318

    Article  CAS  PubMed  Google Scholar 

  5. Turkez H, Geyikoglu F (2010) Boric acid: a potential chemoprotective agent against aflatoxin b1toxicity in human blood. Cytotechnology 62:157–165

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Penland JG (1998) The importance of boron nutrition for brain and psychological function. Biol Trace Elem Res 66:299–317. https://doi.org/10.1007/bf02783144

    Article  CAS  PubMed  Google Scholar 

  7. Białek M, Czauderna M, Krajewska KA, Przybylski W (2019) Selected physiological effects of boron compounds for animals and humans: a review. J Anim Feed Sci 28:307–320. https://doi.org/10.22358/jafs/114546/2019

    Article  Google Scholar 

  8. Plescia J, Moitessier N (2020) Design and discovery of boronic acid drugs. Eur J Med Chem 195:112270. https://doi.org/10.1016/j.ejmech.2020.112270

    Article  CAS  PubMed  Google Scholar 

  9. Liu Y, Milo LJ Jr, Lai JH (2013) Recent progress in the synthesis of pyridinylboronic acids and esters. ARKIVOC 1:135–153. https://doi.org/10.3998/ark.5550190.0014.104

    Article  Google Scholar 

  10. Fontaine F, Héquet A, Voisin-Chiret AS, Bouillon A, Lesnard A, Cresteil T, Jolivalt C, Rault S (2015) Boronic species as promising inhibitors of the Staphylococcus aureus NorA efflux pump: study of 6-substituted pyridine-3-boronic acid derivatives. Eur J Med Chem 95:185–198. https://doi.org/10.1016/j.ejmech.2015.02.056

    Article  CAS  PubMed  Google Scholar 

  11. Dias V, Junn E, Mouradian MM (2013) The role of oxidative stress in Parkinson’s disease. J Parkinsons Dis 3(4):461–491. https://doi.org/10.3233/JPD-130230

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Cuadrado A, Moreno-Murciano P, Pedraza-Chaverri J (2009) The transcription factor Nrf2 as a new therapeutic target in Parkinson’s disease. Expert Opin Ther Targets 13(3):319–329

    Article  CAS  PubMed  Google Scholar 

  13. Vaz RL, Outeiro TF, Ferreira JJ (2018) Zebrafish as an animal model for drug discovery in Parkinson’s disease and other movement disorders: a systematic review. Front Neurol 9:347. https://doi.org/10.3389/fneur.2018.00347

    Article  PubMed  PubMed Central  Google Scholar 

  14. Ünal İ, Emekli-Alturfan E (2019) Fishing for Parkinson’s disease: a review of the literature. J Clin Neurosci 62:1–6. https://doi.org/10.1016/j.jocn.2019.01.015

    Article  PubMed  Google Scholar 

  15. Bhurtel S, Katila N, Srivastav S, Neupane S, Choi DY (2019) Mechanistic comparison between MPTP and rotenone neurotoxicity in mice. Neurotoxicology 71:113–121. https://doi.org/10.1016/j.neuro.2018.12.009

    Article  CAS  PubMed  Google Scholar 

  16. Giordano S, Lee J, Darley-Usmar VM, Zhang J (2012) Distinct effects of rotenone, 1-methyl-4-phenylpyridinium and 6-hydroxydopamine on cellular bioenergetics and cell death. PLoS ONE 7(9):e44610. https://doi.org/10.1371/journal.pone.0044610

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Nicklas WJ, Vyas I, Heikkila RE (1985) Inhibition of NADH-linked oxidation in brain mitochondria by 1-methyl-4-phenyl-pyridine, a metabolite of the neurotoxin, 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine. Life Sci 36:2503–2508. https://doi.org/10.1016/0024-3205(85)90146-8

    Article  CAS  PubMed  Google Scholar 

  18. Üstündağ FD, Ünal İ, Cansız D, Üstündağ ÜV, Subaşat HK, Alturfan AA, Tiber PM, Emekli-Alturfan E (2020) 3-Pyridinylboronic acid normalizes the effects of 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine exposure in zebrafish embryos. Drug Chem Toxicol. https://doi.org/10.1080/01480545.2020.1795189

    Article  PubMed  Google Scholar 

  19. Yahsi Y, Gungor E, Kara H (2015) Chlorometallate-pyridinium boronic acid salts for Crystal engineering: synthesis of one-, two-, and three-dimensional hydrogen bond networks. Cryst Growth Des 15:2652–2660. https://doi.org/10.1021/cg501769b

    Article  CAS  Google Scholar 

  20. Westerfield M (1995) The zebrafish book: a guide for the laboratory use of zebrafish. University of Oregon Press, Eugene, OR

    Google Scholar 

  21. Goody MF, Kelly MW, Reynolds CJ, Khalil A, Crawford BD, Henry CA (2012) NAD + biosynthesis ameliorates a zebrafish model of muscular dystrophy. PLoS Biol 10:e1001409. https://doi.org/10.1371/journal.pbio.1001409

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real- time quantitative PCR and the 2ΔΔCT method. Methods 25:402–408. https://doi.org/10.1006/meth.2001.1262

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  24. Yagi K (1984) Assay for blood plasma or serum. Methods Enzymol 105:328–337. https://doi.org/10.1016/S0076-6879(84)05042-4

    Article  CAS  PubMed  Google Scholar 

  25. Miranda KM, Espey MG, Wink DA (2001) A rapid, simple spectrophotometric method for simultaneous detection of nitrate and nitrite. Nitric Oxide—Biol Chem 5:62–71. https://doi.org/10.1006/niox.2000.0319

    Article  CAS  Google Scholar 

  26. Beutler E (1975) Glutathione in red cell metabolism : a manual of Biochemical methods, 2nd edn. Grune and Stratton, NY, pp 112–114

    Google Scholar 

  27. Habig WH, Jakoby WB (1981) Assays for differentiation of glutathione S-transferases. Methods Enzymol 77:398–405. https://doi.org/10.1016/S0076-6879(81)77053-8

    Article  CAS  PubMed  Google Scholar 

  28. Vomund S, Schäfer A, Parnham MJ, Brüne B, von Knethen A (2017) Nrf2, the master regulator of anti-oxidative responses. Int J Mol Sci 18:2772. https://doi.org/10.3390/ijms18122772

    Article  CAS  PubMed Central  Google Scholar 

  29. Ramsay RR, Singer TP (1986) Energy-dependent uptake of N-methyl-4-phenylpyridinium, the neurotoxic metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, by mitochondria. J Biol Chem 261:7585–7587. https://doi.org/10.1016/S0021-9258(19)57434-8

    Article  CAS  PubMed  Google Scholar 

  30. Moscovitz O, Ben-Nissan G, Fainer I, Pollack D, Mizrachi L, Sharon M (2015) The Parkinson’s-associated protein DJ-1 regulates the 20S proteasome. Nat Commun 6:6609. https://doi.org/10.1038/ncomms7609

    Article  CAS  PubMed  Google Scholar 

  31. Hayes JD, Flanagan JU, Jowsey IR (2005) Glutathione transferases. Annu Rev Pharmacol Toxicol 45:51–88

    Article  CAS  PubMed  Google Scholar 

  32. Dhakshinamoorthy S, Long DJ, Jaiswal AK (2000) Antioxidant regulation of genes encoding enzymes that detoxify xenobiotics and carcinogens. Curr Top Cell Regul. 36:201–216

    Article  CAS  PubMed  Google Scholar 

  33. Kurutas EB (2016) The importance of antioxidants which play the role in cellular response against oxidative/nitrosative stress: current state. Nutr J 15(1):71. https://doi.org/10.1186/s12937-016-0186-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Oh ET, Park HJ (2015) Implications of NQO1 in cancer therapy. BMB Rep 48(11):609–617

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Poss KD, Tonegawa S (1997) Reduced stress defense in heme oxygenase 1-deficient cells. Proc Natl Acad Sci USA 94(20):10925–10930

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Krejsa CM, Franklin CC, White CC, Ledbetter JA, Schieven GL, Kavanagh TJ (2010) Rapid activation of glutamate cysteine ligase following oxidative stress. J Biol Chem 285(21):16116–16124

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Fujii J, Ito JI, Zhang X, Kurahashi T (2011) Unveiling the roles of the glutathione redox system in vivo by analyzing genetically modified mice. J Clin Biochem Nutr 49(2):70–78. https://doi.org/10.3164/jcbn.10-138SR

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Hunt CD, Idso JP (1999) Dietary boron as a phys-iological regulator of the normal inflammatory response: a review and current research progress. J Trace Elem Exp Med 12:221–233. https://doi.org/10.1002/(SICI)1520-670X(1999)12:3%3C221::AIDJTRA6%3E3.0.CO;2-X

    Article  CAS  Google Scholar 

  39. Kucukkurt I, Ince S, Demirel HH, Turkmen R, Akbel E, Celik Y (2015) The effects of boron on arsenic-induced lipid peroxidation and antioxidant status in male and female rats. J Biochem Mol Toxicol 29(12):564–571

    Article  CAS  PubMed  Google Scholar 

  40. Nielsen FH (2009) Boron deprivation decreases liver S-adenosylmethionine and spermidine and increases plasma homocysteine and cysteine in rats. J Trace Elem Med Biol 23(3):204–213

    Article  CAS  PubMed  Google Scholar 

  41. Hoffman DJ, Sanderson CJ, Le Captain LJ, Crom-artie E, Pendleton GW (1992) Interactive ef-fects of selenium, methionine, and dietary protein onsurvival, growth, and physiology in mallard ducklings. Arch Environ Contam Toxicol 23:163–171. https://doi.org/10.1007/BF00213302

    Article  CAS  PubMed  Google Scholar 

  42. Al-Saleh IA, Al-Doush I (1997) Selenium levelsin wheat grains grown in Saudi Arabia. Bull Environ Contam Toxicol 59:590–594

    Article  CAS  PubMed  Google Scholar 

  43. Gülsoy N, Yavas C, Mutlu Ö (2015) Genotoxic effects of boric acid and borax in zebrafish, Danio rerio using alkaline comet assay. EXCLI J. 14:890–899. https://doi.org/10.17179/excli2015-404

    Article  PubMed  PubMed Central  Google Scholar 

  44. Heindel JJ, Price CJ, Schwetz BA (1994) The developmental toxicity of boric acid in mice, rats, and rabbits. Environmental Health Perspectives 102(Suppl 7):107–112

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Naghii MR, Mofid M, Asgari AR, Hedayati M, Daneshpour MS (2011) Comparative effects of daily and weekly boron supplementation on plasma steroid hormones and proinflammatory cytokines. J Trace Elem Med Biol 25:54–58. https://doi.org/10.1016/j.jtemb.2010.10.001

    Article  CAS  PubMed  Google Scholar 

  46. Stefanis L, Burke RE, Greene LA (1997) Apoptosis in neurodegenerative disorders. Curr Opin Neurol 10:299–305

    Article  CAS  PubMed  Google Scholar 

  47. Penland JG (1994) Dietary boron, brain function, and cognitive performance. Environ Health Perspect 102:65–72. https://doi.org/10.1289/ehp.94102s765

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Pizzorno L (2015) Nothing boring about boron. Integr Med (Encinitas) 14:35–48

    Google Scholar 

  49. Jiang L, Zhang H, Wang C, Ming F, Shi X, Yang M (2019) Serum level of brain-derived neurotrophic factor in Parkinson’s disease: a meta-analysis. Prog Neuropsychopharmacol Biol Psychiatry 10(88):168–174. https://doi.org/10.1016/j.pnpbp.2018.07.010

    Article  CAS  Google Scholar 

Download references

Funding

The authors have not disclosed any funding.

Author information

Authors and Affiliations

  1. Institute of Health Sciences, Department of Biophysics, Marmara University, Istanbul, Turkey

    Fümet Duygu Üstündağ

  2. Institute of Health Sciences, Department of Biochemistry, Marmara University, Istanbul, Turkey

    İsmail Ünal, Merih Beler & Atakan Karagöz

  3. Faculty of Medicine, Medical Biochemistry, Istanbul Medipol University, Istanbul, Turkey

    Ünsal Veli Üstündağ & Derya Cansız

  4. Faculty of Medicine, Department of Biochemistry, Istanbul University-Cerrahpaşa, Istanbul, Turkey

    A. Ata Alturfan

  5. Graduate School of Natural and Applied Sciences, Department of Energy, Mugla Sıtkı Kocman University, Muğla, Turkey

    Hülya Kara Subaşat

  6. Faculty of Medicine, Department of Biophysics, Marmara University, Istanbul, Turkey

    Pınar Mega Tiber

  7. Faculty of Dentistry, Department of Basic Medical Sciences, Marmara University, Istanbul, Turkey

    Ebru Emekli-Alturfan

Authors
  1. Fümet Duygu Üstündağ
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. İsmail Ünal
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ünsal Veli Üstündağ
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Derya Cansız
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Merih Beler
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Atakan Karagöz
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Hülya Kara Subaşat
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. A. Ata Alturfan
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Pınar Mega Tiber
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Ebru Emekli-Alturfan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ebru Emekli-Alturfan.

Ethics declarations

Conflict of Interest

The authors report no conflicts of interest.

Ethical Approval

As the zebrafish embryos used were no older than 5 days old, no ethical approval was required for the protocols applied as stated by the Council of Europe (1986), Directive 86/609/EEC.

Consent to Participate

All the authors have agreed for authorship, read and approved the manuscript, and given consent to participate.

Consent for Publication

All the authors have agreed for authorship, read and approved the manuscript, and given consent for publication.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Üstündağ, F.D., Ünal, İ., Üstündağ, Ü.V. et al. 3-Pyridinylboronic Acid Ameliorates Rotenone-Induced Oxidative Stress Through Nrf2 Target Genes in Zebrafish Embryos. Neurochem Res 47, 1553–1564 (2022). https://doi.org/10.1007/s11064-022-03548-6

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11064-022-03548-6

Keywords

Search

Navigation