Skip to main content
SpringerLink
Log in

Chronic Treatment with Paraquat Induces Brain Injury, Changes in Antioxidant Defenses System, and Modulates Behavioral Functions in Zebrafish

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

Paraquat (PQ) administration consists in a chemical model that mimics phenotypes observed in Parkinson’s disease (PD), due to its ability to induce changes in dopaminergic system and oxidative stress. The aim of this study was to evaluate the actions of PQ in behavioral functions of adult zebrafish and its influence on oxidative stress biomarkers in brain samples. PQ (20 mg/kg) was administered intraperitoneally with six injections for 16 days (one injection every 3 days). PQ-treated group showed a significant decrease in the time spent in the bottom section and a shorter latency to enter the top area in the novel tank test. Moreover, PQ-exposed fish showed a significant decrease in the number and duration of risk assessment episodes in the light–dark test, as well as an increase in the agonistic behavior in the mirror-induced aggression (MIA) test. PQ induced brain damage by decreasing mitochondrial viability. Concerning the antioxidant defense system, PQ increased catalase (CAT) and glutathione peroxidase (GPx) activities, as well as the non-protein sulfhydryl content (NPSH), but did not change ROS formation and decreased lipid peroxidation. We demonstrate, for the first time, that PQ induces an increase in aggressive behavior, alters non-motor patterns associated to defensive behaviors, and changes redox parameters in zebrafish brain. Overall, our findings may serve as useful tools to investigate the interaction between behavioral and neurochemical impairments triggered by PQ administration in zebrafish.

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

Similar content being viewed by others

References

  1. Boithias L, Sauvage S, Taghavi L, Merlina G, Probst JL, Sánchez Pérez JM (2011) Occurrence of metolachlor and trifluralin losses in the save river agricultural catchment during floods. J Hazard Mater 196:210–219. doi:10.1016/j.jhazmat.2011.09.012

    Article  CAS  PubMed  Google Scholar 

  2. Houze PFJ, Baud R, Mouy C, Bismuth R, Bourdon R, Scherrmann JM (1990) Toxicokinetics of paraquat in humans. Hum Exp Toxicol 9:5–12

    Article  CAS  PubMed  Google Scholar 

  3. Ogata T, Manabe S (1990) Correlation between lipid peroxidation and morphological manifestation of paraquat-induced lung injury in rats. Arch Toxicol 64:7–13

    Article  CAS  PubMed  Google Scholar 

  4. Satoh M, Naganuma A, Imura N (1992) Effect of preinduction of metallothionein on paraquat toxicity in mice. Arch Toxicol 66:145–148

    Article  CAS  PubMed  Google Scholar 

  5. Manning-Bog AB, McCormack AL, Purisai MG, Bolin LM, Di Monte DA (2003) Alpha-synuclein overexpression protects against paraquat-induced neurodegeneration. J Neurosci 23:3095–3099

    CAS  PubMed  Google Scholar 

  6. McCormack AL, Atienza JG, Langston JW, Di Monte DA (2006) Decreased susceptibility to oxidative stress underlies the resistance of specific dopaminergic cell populations to paraquat-induced degeneration. Neuroscience 141:929–937

    Article  CAS  PubMed  Google Scholar 

  7. Cocheme HM, Murphy MP (2008) Complex I is the major site of mitochondrial superoxide production by paraquat. J Biol Chem 283:1786–1798

    Article  CAS  PubMed  Google Scholar 

  8. Dinis-Oliveira RJ, Remiao F, Carmo H, Duarte JÁ, Navarro AS, Bastos ML, Carvalho F (2006) Paraquat exposure as an etiological factor of Parkinson’s disease. Neurotoxicology 27:1110–1122

    Article  CAS  PubMed  Google Scholar 

  9. Jackson-Lewis V, Blesa J, Przedborski S (2012) Animal models of Parkinson’s disease. Parkinsonism Relat Disord 1:183–185. doi:10.1016/S1353-8020(11)70057-8

    Article  Google Scholar 

  10. Ng F, Berk M, Dean O, Bush AI (2008) Oxidative stress in psychiatric disorders: evidence base and therapeutic implications. Int J Neuropsychopharmacol 11:851–876. doi:10.1017/S1461145707008401

    Article  CAS  PubMed  Google Scholar 

  11. Halliwell B (2006) Oxidative stress and neurodegeneration: where are we now? J Neurochem 97:1634–1658

    Article  CAS  PubMed  Google Scholar 

  12. Shimizu K, Matsubara K, Ohtaki K, Fujimaru S, Saito O, Shiono H (2003) Paraquat induces long-lasting dopamine overflow through the excitotoxic pathway in the striatum of freely moving rats. Brain Res 976:243–252

    Article  CAS  PubMed  Google Scholar 

  13. Litteljohn D, Mangano E, Shukla N, Hayley S (1906) Interferonc deficiency modifies the motor and co-morbid behavioral pathology and neurochemical changes provoked by the pesticide paraquat. Neuroscience 164:1894–1906

    Article  Google Scholar 

  14. Czerniczyniec A, Karadayaian AG, Bustamante J, Cutrera RA, Lores-Arnaiz S (2011) Paraquat induces behavioral changes and cortical and striatal mitochondrial dysfunction. Free Radic Biol Med 51:1428–1436

    Article  CAS  PubMed  Google Scholar 

  15. Rammal H, Bouayed J, Younos C, Soulimani R (2008) The impact of high anxiety levels on the oxidative status of mouse peripheral blood lymphocytes, granulocytes and monocytes. Eur J Pharmacol 589:173–175. doi:10.1016/j.ejphar.2008.06.053

    Article  CAS  PubMed  Google Scholar 

  16. Bortolotto JW, Cognato GP, Cristoff RR, Roesler LN, Leite CE, Kist LW, Bogo MR, Vianna MR et al (2014) Long-term exposure to paraquat alters behavioral parameters and dopamine levels in adult zebrafish (Danio Rerio). Zebrafish 11:142–153. doi:10.1089/zeb.2013.0923

    Article  CAS  PubMed  Google Scholar 

  17. Bretaud S, Lee S, Guo S (2004) Sensitivity of zebrafish to environmental toxins implicated in Parkinson’s disease. Neurotoxicol Teratol 26:857–864

    Article  CAS  PubMed  Google Scholar 

  18. Panula P, Sallinen V, Sundvik M, Kolehmainen J, Torkko V, Tiittula A, Moshnyakov M, Podlasz P (2006) Modulatory neurotransmitter systems and behavior: towards zebrafish models of neurodegenerative diseases. Zebrafish 3:235–247. doi:10.1089/zeb.2006.3.235

    Article  CAS  PubMed  Google Scholar 

  19. Flinn L, Bretaud S, Lo C, Ingham PW, Bandmann O (2008) Zebrafish as a new model for movement disorders. J Neurochem 106:1991–1997. doi:10.1111/j.1471-4159.2008.05463.x

    Article  CAS  PubMed  Google Scholar 

  20. Egan RJ, Bergner CL, Hart PC, Cachat JM, Canavello PR, Elegante MF et al (2009) Understanding behavioral and physiological phenotypes of stress and anxiety in zebrafish. Behav Brain Res 205:38–44. doi:10.1016/j.bbr.2009.06.022

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Gerlai R (2012) Using zebrafish to unravel the genetics of complex brain disorders. Curr Top in Behav Neurosci 12:3–24. doi:10.1007/7854_2011_180

    Article  Google Scholar 

  22. Rosemberg DB, Braga MM, Rico EP, Loss CM, Córdova SD, Mussulini BH (2012) Behavioral effects of taurine pretreatment in zebrafish acutely exposed to ethanol. Neuropharmacology 63:613–623. doi:10.1016/j.neuropharm.2012.05.009

    Article  CAS  PubMed  Google Scholar 

  23. Barbazuk WB, Korf I, Kadavi C, Heyen J, Tate S, Wun E (2000) The synthetic relationship of the zebrafish and human genomes. Genome Res 10:1351–1358

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Almeida JA, Barreto RE, Novelli ELB, Castro FJ, Moron SE (2009) Oxidative stress biomarkers and aggressive behavior in fish exposed to aquatic cadmium contamination. Neotrop Ichthyol 7:103–108

    Article  Google Scholar 

  25. Cachat J, Stewart A, Grossman L, Gaikwad S, Kadri F, Chung KM et al (2010) Measuring behavioral and endocrine responses to novelty stress in adult zebrafish. Nat Protoc 5:1786–1799

    Article  CAS  PubMed  Google Scholar 

  26. Rosemberg DB, Rico EP, Mussulini BH, Piato AL, Calcagnotto ME, Bonan CD et al (2011) Differences in spatio-temporal behavior of zebrafish in the open tank paradigm after a short-period confinement into dark and bright environments. PLoS One. doi:10.1371/journal.pone.0019397

    PubMed  PubMed Central  Google Scholar 

  27. Maximino C, Marques de Brito T, Dias CA, Gouveia A Jr, Morato S (2010) Scototaxis as anxiety-like behavior in fish. Nat Protoc 5:209–216. doi:10.1038/nprot.2009.225

    Article  CAS  PubMed  Google Scholar 

  28. Kalueff AV, Gebhardt M, Stewart AM, Cachat JM, Brimmer M, Chawla JS et al (2013) Towards a comprehensive catalog of zebrafish behavior 1.0 and beyond. Zebrafish 10:70–86. doi:10.1089/zeb.2012.0861

    Article  PubMed  PubMed Central  Google Scholar 

  29. Gerlai R, Lahav M, Guo S, Rosenthal A (2000) Drinks like a fish: zebra fish (Danio rerio) as a behavior genetic model to study alcohol effects. Pharmacol Biochem Behav 67:773–782

    Article  CAS  PubMed  Google Scholar 

  30. Wilson JM, Bunte RM, Carty AJ (2009) Evaluation of rapid cooling and tricaine methanesulfonate (MS222) as methods of euthanasia in zebrafish (Danio rerio). J Am Assoc Lab Anim Sci 48:785–789

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Preston P, Webster J (2000) Spectrophotometric measurement of experimental brain injury. J Neurosci Methods 94:187–192

    Article  CAS  PubMed  Google Scholar 

  32. Braga MM, Rico EP, Córdova SD, Pinto CB, Blaser RE, Dias RD, Rosemberg DB, Oliveira DL et al (2013) Evaluation of spontaneous recovery of behavioral and brain injury profiles in zebrafish after hypoxia. Behav Brain Res 253:145–151. doi:10.1016/j.bbr.2013.07.019

    Article  CAS  PubMed  Google Scholar 

  33. Draper HH, Hadley M (1990) Malondialdehyde determination as index of lipid peroxidation. Methods Enzymol 186:421–431

    Article  CAS  PubMed  Google Scholar 

  34. Ali SF, LeBel CP, Bondy SC (1992) Reactive oxygen species formation as a biomarker of methylmercury and trimethyltin neurotoxicity. Neurotoxicology 13:637–648

    CAS  PubMed  Google Scholar 

  35. Aebi H (1984) Catalase in vitro. Methods Enzymol 105:121–126

    Article  CAS  PubMed  Google Scholar 

  36. Paglia DE, Valentine WN (1967) Studies on the quantitative and qualitative characterization of erythrocyte glutathione peroxidase. J Lab Clin Med 70:158–169

    CAS  PubMed  Google Scholar 

  37. Habig WH, Pabst MJ, Jacoby WB (1974) Glutathione S-transferase, the first enzymatic step in mercapturic acid formation. J Biol Chem 249:7130–7139

    CAS  PubMed  Google Scholar 

  38. Ellman GL (1959) Tissue sulfhydryl groups. Arch Biochem Biophys 82:70–77

    Article  CAS  PubMed  Google Scholar 

  39. 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

    Article  CAS  PubMed  Google Scholar 

  40. Shepherd KR, Lee EY, Schmued L, Jiao Y, Ali SF, Oriaku ET, Lamango NS et al (2006) The potentiating effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on paraquat-induced neurochemical and behavioral changes in mice. Pharmacol Biochem Behav 83:349–359

    Article  CAS  PubMed  Google Scholar 

  41. Szabó A, Nemcsók J, Asztalos B, Rakonczay Z, Kása P, Hieu LH (1992) The effect of pesticides on carp (Cyprinus carpio L). Acetylcholinesterase and its biochemical characterization. Ecotoxicol Environ Saf 23:39–45

    Article  PubMed  Google Scholar 

  42. Brown TP, Rumsby PC, Capleton AC, Rushton L, Levy LS (2006) Pesticides and Parkinson’s disease is there a link? Environ Health Perspect 114:156–164

    Article  PubMed  Google Scholar 

  43. Kamel F, Tanner C, Umbach D, Hoppin J, Alavamja M, Blair A et al (2007) Pesticide exposure and self reported Parkinson’s disease in the agricultural health study. Am J Epidemiol 165:364–374

    Article  CAS  PubMed  Google Scholar 

  44. Jimenez-Del-Rio M, Guzman-Martinez C, Velez-Pardo C (2010) Effects of polyphenols on survival and locomotor activity in Drosophila Melanogaster exposed to iron and paraquat. Neurochem Res 35:227–238. doi:10.1007/s11064-009-0046-1

    Article  CAS  PubMed  Google Scholar 

  45. Stallones L, Beseler C (2002) Pesticide poisoning and depressive symptoms among farm residents. Ann Epidemiol 12(6):389–394

    Article  PubMed  Google Scholar 

  46. Farahat TM, Abdelrasoul GM, Amr MM, Shebl MM, Farahat FM, Anger WR (2003) Neurobehavioural effects among workers occupationally exposed to organophosphorous pesticides. Occup Environ Med 60:279–286. doi:10.1136/oem.60.4.279

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Chaudhuri KR, Healy DG, Schapira AHV (2006) Non-motor symptoms of Parkinson’s disease: diagnosis and management. Lancet Neurol 5:235–245

    Article  PubMed  Google Scholar 

  48. Langston JW (2006) The Parkinson’s complex: parkinsonism is just the tip of the iceberg. Ann Neurol 59:591–596

    Article  PubMed  Google Scholar 

  49. Taylor TN, Caudle WM, Shepherd KR, Noorian A, Jackson CR, Iuvone PM, Weinshenker D, Greene JG et al (2009) Nonmotor symptoms of Parkinson’s disease revealed in an animal model with reduced monoamine storage capacity. J Neurosci 29:8103–8113. doi:10.1523/JNEUROSCI

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Stanley B, Molcho A, Stanley M, Winchel R, Gameroff MJ, Parsons B et al (2000) Association of aggressive behavior with altered serotonergic function in patients who are not suicidal. Am J Psychiatry 157:609–614

    Article  CAS  PubMed  Google Scholar 

  51. Coccaro EF (1992) Impulsive aggression and central serotonergic system function in humans: an example of a dimensional brain-behavior relationship. Int Clin Psychopharmacol 7:3–12

    Article  CAS  PubMed  Google Scholar 

  52. Coccaro EF, Kavoussi RJ, Hauger RL (1997) Serotonin function and antiaggressive response to fluoxetine: a pilot study. Biol Psychiatry 42:546–552

    Article  CAS  PubMed  Google Scholar 

  53. Zajicek KB, Price CS, Shoaf SE, Mehlman PT, Suomi SJ, Linnoila M et al (2000) Seasonal variation in CSF 5-HIAA concentrations in male rhesus macaques. Neuropsychopharmacology 22:240–250. doi:10.1016/S0893-133X(99)00097-4

    Article  CAS  PubMed  Google Scholar 

  54. Mosienko V, Bert B, Beis D, Matthes S, Fink H, Bader M, Alenina N (2012) Exaggerated aggression and decreased anxiety in mice deficient in brain serotonin. Transl Psychiatry. doi:10.1038/tp.2012.44

    PubMed  PubMed Central  Google Scholar 

  55. Glisic B, Mihaljevi I, Popovic M, Zaja R, Loncar J, Fent K, Kovacevic R, Smital T (2015) Characterization of glutathione-S-transferases in zebrafish (Danio rerio). Aquat Toxicol 158:50–62

    Article  CAS  PubMed  Google Scholar 

  56. Keppler D (1999) Export pumps for glutathione S-conjugates. Free Radic Biol Med 27:985–991

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  58. Castello PR, Drechsel DA, Patel M (2007) Mitochondria are a major source of paraquat-induced reactive oxygen species production in the brain. J Biol Chem 282:14186–14193. doi:10.1074/jbc.M700827200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

We would like to thank the Federal University of Santa Maria for the support and facilities and the financial support and fellowships from the Brazilian agency CAPES (Coordination for the Improvement of Higher Education Personnel). V.L.L. and D.B.R. are recipients of CNPq (National Counsel of Technological and Scientific Development) research productivity grant (312983/2013-1, 307595/2015-3, respectively).

Author information

Authors and Affiliations

  1. Programa de Pós-Graduação em Bioquímica Toxicológica e Biodiversidade Animal, Laboratório de Toxicologia Aquática, Universidade Federal de Santa Maria, Santa Maria, RS, 97105-900, Brazil

    Mauro E. Nunes, Talise E. Müller, Marcos M. Braga, Barbara D. Fontana, Vanessa A. Quadros, Cíntia Rodrigues, Denis B. Rosemberg & Vania Lucia Loro

  2. Programa de Pós-Graduação em Biodiversidade Animal, Centro de Ciências Naturais e Exatas, Universidade Federal de Santa Maria, Santa Maria, RS, Brazil

    Aline Marins, Charlene Menezes & Vania Lucia Loro

Authors
  1. Mauro E. Nunes
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Talise E. Müller
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Marcos M. Braga
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Barbara D. Fontana
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Vanessa A. Quadros
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Aline Marins
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Cíntia Rodrigues
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Charlene Menezes
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Denis B. Rosemberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Vania Lucia Loro
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Vania Lucia Loro.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Nunes, M.E., Müller, T.E., Braga, M.M. et al. Chronic Treatment with Paraquat Induces Brain Injury, Changes in Antioxidant Defenses System, and Modulates Behavioral Functions in Zebrafish. Mol Neurobiol 54, 3925–3934 (2017). https://doi.org/10.1007/s12035-016-9919-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-016-9919-x

Keywords

Search

Navigation