Neurochemical Research

, Volume 37, Issue 5, pp 1102–1111 | Cite as

Investigate the Chronic Neurotoxic Effects of Diquat

  • Senthilkumar S. Karuppagounder
  • Manuj Ahuja
  • Manal Buabeid
  • Koodeswaran Parameshwaran
  • Engy Abdel-Rehman
  • Vishnu Suppiramaniam
  • Muralikrishanan Dhanasekaran
Original Paper


Chronic exposure to agricultural chemicals (pesticides/herbicides) has been shown to induce neurotoxic effects or results in accumulation of various toxic metabolic by-products. These substances have the relevant ability to cause or increase the risk for neurodegeneration. Diquat is an herbicide that has been extensively used in the United States of America and other parts of the world. Diquat is constantly released into the environment during its use as a contact herbicide. Diquat structurally resembles 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP) and paraquat. Rotenone, paraquat, maneb and MPTP reproduce features of movement disorders in experimental animal models. Based on the structural similarity to other neurotoxins, chronic exposure of diquat can induce behavioral and neurochemical alterations associated with dopaminergic neurotoxicity. However, in the present study, diquat unlike other neurotoxins (rotenone, 6-hydroxydopamine, MPTP, paraquat and maneb) did not induce dopamine depletion in the mouse striatum. Although, notable exacerbation in motor impairment (swimming score, akinesia and open field) were evident that may be due to the decreased dopamine turnover and mild nigrostriatal neurodegeneration. These data indicate that, despite the apparent structural similarity to other dopaminergic neurotoxins, diquat did not exert severe deleterious effects on dopamine neurons in a manner that is unique to rotenone and MPTP.


Parkinson’s disease Herbicides Diquat Dopamine Movement disorder Neurotoxicity Environmental toxins 


  1. 1.
    Anton P, Theodorou V, Fioramonti J, Bueno L (1998) Low-Level exposure to diquat induces a neurally mediated intestinal hypersecretion in rats: involvement of nitric oxide and mast cells. Toxicol Appl Pharmacol 152:77–82PubMedCrossRefGoogle Scholar
  2. 2.
    Jones G, Vale J (2000) Mechanisms of toxicity, clinical features, and management of diquat poisoning: a review. J Toxicol Clin Toxicol 38:123–128PubMedCrossRefGoogle Scholar
  3. 3.
    Xu J, Sun S, Wei W, Fu J, Qi W, Manchester L, Tan D, Reiter R (2007) Melatonin reduces mortality and oxidatively mediated hepatic and renal damage due to diquat treatment. J Pineal Res 42:166–171PubMedCrossRefGoogle Scholar
  4. 4.
    Ariffin M, Anderson R (2006) LC/MS/MS analysis of quaternary ammonium drugs and herbicides in whole blood. J Chromatogr B Anal Technol Biomed Life Sci 842:91–97CrossRefGoogle Scholar
  5. 5.
    Nieto M, Gil-Bea F, Dalfó E, Cuadrado M, Cabodevilla F, Sánchez B, Catena S, Sesma T, Ribé E, Ferrer I, Ramírez M, Gómez-Isla T (2006) Increased sensitivity to MPTP in human [alpha]-synuclein A30P transgenic mice. Neurobiol Aging 27:848–856PubMedCrossRefGoogle Scholar
  6. 6.
    Report from Food and Agricultural Organization (FAO) for the United Nations.
  7. 7.
    Morrison H, Wilkins K, Semenciw R, Mao Y, Wigle D (1992) Herbicides and cancer. J Natl Cancer Inst 84:1866–1874PubMedCrossRefGoogle Scholar
  8. 8.
    Bonneh-Barkay D, Langston W, Di Monte D (2005) Toxicity of redox cycling pesticides in primary mesencephalic cultures. Antioxid Redox Signal 7:649–653PubMedCrossRefGoogle Scholar
  9. 9.
    Bonneh-Barkay D, Reaney S, Langston W, Di Monte D (2005) Redox cycling of the herbicide paraquat in microglial cultures. Brain Res Mol Brain Res 134:52–56PubMedCrossRefGoogle Scholar
  10. 10.
    Dinis-Oliveira R, Remiao F, Carmo H, Duarte J, Navarro A, Bastos M, Carvalho F (2006) Paraquat exposure as an etiological factor of Parkinson’s disease. Neurotoxicology 27:1110–1122PubMedCrossRefGoogle Scholar
  11. 11.
    Kamel F, Hoppin J (2004) Association of pesticide exposure with neurologic dysfunction and disease. Environ Health Perspect 112:950–958PubMedCrossRefGoogle Scholar
  12. 12.
    Sechi G, Agnetti V, Piredda M, Canu M, Deserra F, Omar H, Rosati G (1992) Acute and persistent Parkinsonism after use of diquat. Neurology 42:261–263PubMedGoogle Scholar
  13. 13.
    Thiruchelvam M, Richfield E, Baggs R, Tank A, Cory-Slechta D (2000) The nigrostriatal dopaminergic system as a preferential target of repeated exposures to combined paraquat and maneb: implications for Parkinson’s disease. J Neurosci 20:9207–9214PubMedGoogle Scholar
  14. 14.
    Thrash B, Uthayathas S, Karuppagounder S, Suppiramaniam V, Dhanasekaran M (2007) Paraquat and maneb induced neurotoxicity. Proc West Pharmacol Soc 50:31–42PubMedGoogle Scholar
  15. 15.
    Cookson M (2005) The biochemistry of Parkinson’s disease. Annu Rev Biochem 74:29–52PubMedCrossRefGoogle Scholar
  16. 16.
    Cornford M, Chang L, Miller B (1995) The neuropathology of Parkinsonism: an overview. Brain Cogn 28:321–341PubMedCrossRefGoogle Scholar
  17. 17.
    Dhanasekaran M, Karuppagounder S, Uthayathas S, Wold L, Parameshwaran K, Jayachandra Babu R, Suppiramaniam V, Brown-Borg H (2008) Effect of dopaminergic neurotoxin MPTP/MPP+ on coenzyme Q content. Life Sci 83:92–95PubMedCrossRefGoogle Scholar
  18. 18.
    Lang A, Lozano A (1998) Parkinson’s disease. First of two parts. N Engl J Med 339:1044–1053PubMedCrossRefGoogle Scholar
  19. 19.
    Olanow C, Tatton W (1999) Etiology and pathogenesis of Parkinson’s disease. Annu Rev Neurosci 22:123–144PubMedCrossRefGoogle Scholar
  20. 20.
    Beal M (2001) Experimental models of Parkinson’s disease. Nat Rev Neurosci 2:325–334PubMedCrossRefGoogle Scholar
  21. 21.
    Bennett D, Beckett L, Murray A, Shannon K, Goetz C, Pilgrim D, Evans D (1996) Prevalence of parkinsonian signs and associated mortality in a community population of older people. N Engl J Med 334:71–76PubMedCrossRefGoogle Scholar
  22. 22.
    Engelender S (2008) Ubiquitination of alpha-synuclein and autophagy in Parkinson’s disease. Autophagy 4:372–374PubMedGoogle Scholar
  23. 23.
    Arima K, Hirai S, Sunohara N, Aoto K, Izumiyama Y, Uéda K, Ikeda K, Kawai M (1999) Cellular co-localization of phosphorylated tau- and NACP/alpha-synuclein-epitopes in Lewy bodies in sporadic Parkinson’s disease and in dementia with Lewy bodies. Brain Res 843:53–61PubMedCrossRefGoogle Scholar
  24. 24.
    Ishizawa T, Matilla P, Davies P, Wang D, Dickson D (2003) Colocalization of tau and alpha-synuclein epitopes in Lewy bodies. J Neuropathol Exp Neurol 62:389–397PubMedGoogle Scholar
  25. 25.
    Dunnett S, Bjorklund A (1999) Prospects for new restorative and neuroprotective treatments in Parkinson’s disease. Nature 399:A32–A39PubMedCrossRefGoogle Scholar
  26. 26.
    Hunter R, Dragicevic N, Seifert K, Choi D, Liu M, Kim H, Cass W, Sullivan P, Bing G (2007) Inflammation induces mitochondrial dysfunction and dopaminergic neurodegeneration in the nigrostriatal system. J Neurochem 100:1375–1386PubMedCrossRefGoogle Scholar
  27. 27.
    Muralikrishnan D, Ebadi M (2001) SKF-38393, a dopamine receptor agonist, attenuates 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurotoxicity. Brain Res 892:241–247PubMedCrossRefGoogle Scholar
  28. 28.
    Sherer T, Betarbet R, Greenamyre J (2002) Environment, mitochondria, and Parkinson’s disease. Neuroscientist 8:192–197PubMedGoogle Scholar
  29. 29.
    Gorell J, Johnson C, Rybicki B, Peterson E, Richardson R (1998) The risk of Parkinson’s disease with exposure to pesticides, farming, well water, and rural living. Neurology 50:1346–1350PubMedGoogle Scholar
  30. 30.
    Menegon A, Board P, Blackburn A, Mellick G, Couteur D (1998) Parkinson’s disease, pesticides, and glutathione transferase polymorphisms. Lancet 352:1344–1346PubMedCrossRefGoogle Scholar
  31. 31.
    Wright J, Keller-Byrne J (2005) Environmental determinants of Parkinson’s disease. Arch Environ Occup Health 60:32–38PubMedCrossRefGoogle Scholar
  32. 32.
    Schober A (2004) Classic toxin-induced animal models of Parkinson’s disease: 6-OHDA and MPTP. Cell Tissue Res 318:215–224PubMedCrossRefGoogle Scholar
  33. 33.
    Yumino K, Kawakami I, Tamura M, Hayashi T, Nakamura M (2002) Paraquat-and diquat-induced oxygen radical generation and lipid peroxidation in rat brain microsomes. J Biochem 131:565PubMedCrossRefGoogle Scholar
  34. 34.
    Rawlings J, Wyatt I, Heylings J (1994) Evidence for redox cycling of diquat in rat small intestine. Biochem Pharmacol 47:1271–1274PubMedCrossRefGoogle Scholar
  35. 35.
    Awad J, Burk R, Roberts L (1994) Effect of selenium deficiency and glutathione-modulating agents on diquat toxicity and lipid peroxidation in rats. J Pharmacol Exp Ther 270:858–864PubMedGoogle Scholar
  36. 36.
    Higuchi M, Kobayashi S, Kawasaki N, Hamaoka K, Watabiki S, Orino K, Watanabe K (2007) Protective effects of wheat bran against diquat toxicity in male Fischer-344 rats. Biosci Biotechnol Biochem 71:1621–1625PubMedCrossRefGoogle Scholar
  37. 37.
    Zhang L, Wei W, Xu J, Min F, Wang L, Wang X, Cao S, Tan D, Qi W, Reiter R (2006) Inhibitory effect of melatonin on diquat-induced lipid peroxidation in vivo as assessed by the measurement of F2-isoprostanes. J Pineal Res 40:326–331PubMedCrossRefGoogle Scholar
  38. 38.
    Muralikrishnan D, Ebadi M, Brown-Borg H (2002) Effect of MPTP on Dopamine metabolism in Ames dwarf mice. Neurochem Res 27:457–464PubMedCrossRefGoogle Scholar
  39. 39.
    Muralikrishnan D, Mohanakumar K (1998) Neuroprotection by bromocriptine against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurotoxicity in mice. FASEB J 12:905–912PubMedGoogle Scholar
  40. 40.
    Jiao Y, Yan J, Zhao Y, Donahue L, Beamer W, Li X, Roe B, Ledoux M, Gu W (2005) Carbonic anhydrase-related protein VIII deficiency is associated with a distinctive lifelong gait disorder in waddles mice. Genetics 171:1239–1246PubMedCrossRefGoogle Scholar
  41. 41.
    Holcomb L, Dhanasekaran M, Hitt A, Young K, Riggs M, Manyam B (2006) Bacopa monniera extract reduces amyloid levels in PSAPP mice. J Alzheimers Dis 9:243–251PubMedGoogle Scholar
  42. 42.
    Klapdor K, Dulfer B, Hammann A, Van der Staay F (1997) A low-cost method to analyse footprint patterns. J Neurosci Methods 75:49–54PubMedCrossRefGoogle Scholar
  43. 43.
    Senthilkumar K, Saravanan K, Chandra G, Sindhu K, Jayakrishnan A, Mohanakumar K (2007) Unilateral implantation of dopamine-loaded biodegradable hydrogel in the striatum attenuates motor abnormalities in the 6-hydroxydopamine model of hemi-parkinsonism. Behav Brain Res 184:11–18PubMedCrossRefGoogle Scholar
  44. 44.
    Beligni M, Lamattina L (1999) Nitric oxide protects against cellular damage produced by methylviologen herbicides in potato plants. Nitric Oxide 3:199–208PubMedCrossRefGoogle Scholar
  45. 45.
    Broussolle E, Thobois S (2002) Genetics and environmental factors of Parkinson disease. Rev Neurol 158:S11–S23PubMedGoogle Scholar
  46. 46.
    Borland M, Trimmer P, Rubinstein J, Keeney P, Mohanakumar K, Liu L, Bennett J (2008) Chronic, low-dose rotenone reproduces Lewy neurites found in early stages of Parkinson’s disease, reduces mitochondrial movement and slowly kills differentiated SH-SY5Y neural cells. Jr. Mol Neurodegener 3:21CrossRefGoogle Scholar
  47. 47.
    Saravanan K, Sindhu K, Mohanakumar K (2005) Acute intranigral infusion of rotenone in rats causes progressive biochemical lesions in the striatum similar to Parkinson’s disease. Brain Res 1049:147–155PubMedCrossRefGoogle Scholar
  48. 48.
    Saravanan K, Sindhu K, Mohanakumar K (2007) Melatonin protects against rotenone-induced oxidative stress in a hemiparkinsonian rat model. J Pineal Res 42:247–253PubMedCrossRefGoogle Scholar
  49. 49.
    Saravanan K, Sindhu K, Senthilkumar K, Mohanakumar K (2006) L-deprenyl protects against rotenone-induced, oxidative stress-mediated dopaminergic neurodegeneration in rats. Neurochem Int 49:28–40PubMedCrossRefGoogle Scholar
  50. 50.
    Sindhu K, Saravanan K, Mohanakumar K (2005) Behavioral differences in a rotenone-induced hemiparkinsonian rat model developed following intranigral or median forebrain bundle infusion. Brain Res 1051:25–34PubMedCrossRefGoogle Scholar
  51. 51.
    Mohanakumar K, Muralikrishnan D, Thomas B (2000) Neuroprotection by sodium salicylate against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurotoxicity. Brain Res 864:281–290PubMedCrossRefGoogle Scholar
  52. 52.
    Muralikrishnan D, Samantaray S, Mohanakumar K (2003) D-deprenyl protects nigrostriatal neurons against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced dopaminergic neurotoxicity. Synapse 50:7–13PubMedCrossRefGoogle Scholar
  53. 53.
    Hertzman C, Wiens M, Bowering D, Snow B, Calne D (1990) Parkinson’s disease: a case-control study of occupational and environmental risk factors. Am J Ind Med 17:349–355PubMedCrossRefGoogle Scholar
  54. 54.
    Liou H, Tsai M, Chen C, Jeng J, Chang Y, Chen SY (1997) Environmental risk factors and Parkinson’s disease: a case-control study in Taiwan. Neurology 48:1583–1588PubMedGoogle Scholar
  55. 55.
    Semchuk K, Love E, Lee R (1992) Parkinson’s disease and exposure to agricultural work and pesticide chemicals. Neurology 42:1328–1335PubMedGoogle Scholar
  56. 56.
    Hoffman W, Ness D, van Lier R (2002) Analysis of rodent growth data in toxicology studies. Toxicol Sci 66:313–319PubMedCrossRefGoogle Scholar
  57. 57.
    Fredriksson A, Stigsdotter I, Hurtig A, Ewalds-Kvist B, Archer T (2011) Running wheel activity restores MPTP-induced functional deficits. J Neural Transm 118:407–420PubMedCrossRefGoogle Scholar
  58. 58.
    Hutter-Saunders J, Kosloski L, McMillan J, Yotam N, Rinat T, Mosley R, Gendelman H (2011) BL-1023 improves behavior and neuronal survival in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-intoxicated mice. Neuroscience 180:293–304PubMedCrossRefGoogle Scholar
  59. 59.
    Kurosaki R, Muramatsu Y, Kato H, Araki T (2004) Biochemical, behavioral and immunohistochemical alterations in MPTP-treated mouse model of Parkinson’s disease. Pharmacol Biochem Behav 78:143–153PubMedCrossRefGoogle Scholar
  60. 60.
    Jinsmaa Y, Florang V, Rees J, Mexas L, Eckert L, Allen E, Anderson D, Doorn J (2011) Dopamine-derived biological reactive intermediates and protein modifications: implications for Parkinson’s disease. Chem Biol Interact 192:118–121PubMedCrossRefGoogle Scholar
  61. 61.
    Tanner C, Kamel F, Ross G, Hoppin J, Goldman S, Korell M, Marras C, Bhudhikanok G, Kasten M, Chade A, Comyns K, Richards M, Meng C, Priestley B, Fernandez H, Cambi F, Umbach D, Blair A, Sandler D, Langston J (2011) Rotenone, paraquat, and Parkinson’s disease. Environ Health Perspect 119:866–872PubMedCrossRefGoogle Scholar
  62. 62.
    Fischer L, Glass J (2010) Oxidative stress induced by loss of Cu, Zn-superoxide dismutase (SOD1) or superoxide-generating herbicides causes axonal degeneration in mouse DRG cultures. Acta Neuropathol 119:249–259PubMedCrossRefGoogle Scholar
  63. 63.
    Checkoway H, Nelson L (1999) Epidemiologic approaches to the study of Parkinson’s disease etiology. Epidemiology 10:327–336PubMedCrossRefGoogle Scholar
  64. 64.
    Horner JM (1992) Diquat: subchronic neurotoxicity study in rats. ICI Report No. CTL/P/3751. DPR Vol. 226-101 #120427Google Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Senthilkumar S. Karuppagounder
    • 1
  • Manuj Ahuja
    • 1
  • Manal Buabeid
    • 1
  • Koodeswaran Parameshwaran
    • 1
  • Engy Abdel-Rehman
    • 1
  • Vishnu Suppiramaniam
    • 1
  • Muralikrishanan Dhanasekaran
    • 1
  1. 1.Division of Pharmacology and Toxicology, Department of Pharmacal Sciences, Harrison School of PharmacyAuburn UniversityAuburnUSA

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