Summary
Parkinson’s disease (PD) is a common neurodegenerative disease that appears essentially as a sporadic condition. It results mainly from the death of dopaminergic neurons in the substantia nigra. PD etiology remains mysterious, whereas its pathogenesis begins to be understood as a multifactorial cascade of deleterious factors. Most insights into PD pathogenesis come from investigations performed in experimental models of PD, especially those produced by neurotoxins. Although a host of natural and synthetic molecules do exert deleterious effects on dopaminergic neurons, only a handful are used in living laboratory animals to recapitulate some of the hallmarks of PD. In this review, we discuss what we believe are the four most popular parkinsonian neurotoxins, namely 6-hydroxydopamine (6-OHDA), 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), rotenone, and paraquat. The main goal is to provide an updated summary of the main characteristics of each of these four neurotoxins. However, we also try to provide the reader with an idea about the various strengths and the weaknesses of these neurotoxic models.
Article PDF
Similar content being viewed by others
References
Fahn S, Przedborski S. Parkinsonism. In: Merritt’s neurology (Rowland LP, ed), Ed 10, pp 679–693. New York: Lippincott Williams & Wilkins, 2000.
Dauer W, Przedborski S. Parkinson’s disease: mechanisms and models. Neuron 39: 889–909, 2003.
Przedborski S, Goldman JE. Pathogenic role of glial cells in Parkinson’s disease. In: Non-neuronal cells of the nervous system: function and dysfunction (Hertz L, ed), pp 967–982. New York: Elsevier, 2004.
Przedborski S, Tieu K. Toxic animal models. In: Neurodegenerative diseases: neurobiology, pathogenesis and therapeutics (Beal MF, Lang AE, Ludolph A, eds), pp 196–221. New York: Cambridge, 2005.
Przedborski S, Tieu K, Perier C, Vila M. MPTP as a mitochondrial neurotoxic model of Parkinson’s disease. J Bioenerg Biomembr 36: 375–379, 2004.
Przedborski S, Ischiropoulos H. Reactive oxygen and nitrogen species: weapons of neuronal destruction in models of Parkinson’s disease. Antioxid Redox Signaling 7: 685–693, 2005.
Jonsson G. Chemical lesioning techniques: monoamine neurotoxins. In: Handbook of chemical neuroanatomy. Methods in chemical neuroanatomy (Björklund A, Hökfelt T, eds), Ed 1, Vol 1, pp 463–507. Amsterdam: Elsevier Science Publishers B.V., 1983.
Roeling TA, Docter GJ, Voom P, Melchers BP, Wolters EC, Groenewegen HJ. Effects of unilateral 6-hydroxydopamine lesions on neuropeptide immunoreactivity in the basal ganglia of the common marmoset, Callithrix jacchus, a quantitative immunohistochemical analysis. J Chem Neuroanat 9: 155–164, 1995.
Annett LE, Tones EM, Clarke DJ, Ishida Y, Barker RA, Ridley RM, et al. Survival of nigral grafts within the striatum of marmosets with 6-OHDA lesions depends critically on donor embryo age. Cell Transplant 6: 557–569, 1997.
Crofts HS, Dalley JW, Collins P, Van Denderen JC, Everitt BJ, Robbins TW, et al. Differential effects of 6-OHDA lesions of the frontal cortex and caudate nucleus on the ability to acquire an attentional set. Cereb Cortex 11: 1015–1026, 2001.
Ma KH, Huang WS, Chen CH, Lin SZ, Wey SP, Ting G, et al. Dual SPECT of dopamine system using [99mTc]TRODAT-l and [123I]IBZM in normal and 6-OHDA-lesioned formosan rock monkeys. Nucl Med Biol 29: 561–567, 2002.
Soares-da-Silva P, Azevedo I. Differential effects of 6-hydroxydopamine on the two types of nerve vesicles and dopamine and noradrenaline content in mesenteric arterial vessels. J Auton Pharmacol 8: 1–10, 1988.
Valette H, Deleuze P, Syrota A, Delforge J, Crouzel C, Fuseau C, et al. Canine myocardial beta-adrenergic, muscarinic receptor densities after denervation: a PET study. J Nucl Med 36: 140–146, 1995.
Ruffy R, Leonard M. Chemical cardiac sympathetic denervation hampers defibrillation in the dog. J Cardiovasc Electrophysiol 8: 62–67, 1997.
Jonsson G. Chemical neurotoxins as denervation tools in neurobiology. Annu Rev Neurosci 3: 169–187, 1980.
Cohen G. Oxy-radical toxicity in catecholamine neurons. Neurotoxicology 5: 77–82, 1984.
Saner A, Thoenen H. Model experiments on the molecular mechanism of action of 6-hydroxydopamine. Mol Pharmacol 7: 147–154, 1971.
Heikkila R, Cohen G. Inhibition of biogenic amine uptake by hydrogen peroxide: a mechanism for toxic effects of 6-hydroxydopamine. Science 172: 1257–1258, 1971.
Mandel RJ, Randall PK. Quantification of lesion-induced dopaminergic supersensitivity using the rotational model in mouse. Brain Res 330: 358–363, 1985.
He Y, Appel S, Le W. Minocycline inhibits microglial activation and protects nigral cells after 6-hydroxydopamine injection into mouse striatum. Brain Res 909: 187–193, 2001.
Lundblad M, Picconi B, Lindgren H, Cenci MA. A model of L-DOPA-induced dyskinesia in 6-hydroxydopamine lesioned mice: relation to motor and cellular parameters of nigrostriatal function. Neurobiol Dis 16: 110–123, 2004.
Baker SA, Baker KA, Hagg T. Dopaminergic nigrostriatal projections regulate neural precursor proliferation in the adult mouse subventricular zone. Eur J Neurosci 20: 575–579, 2004.
Ungerstedt U. Adipsia and aphagia after 6-hydroxydopamine induced degeneration of the nigro-striatal dopamine system. Acta Physiol Scand Suppl 367: 95–122, 1971.
Bourn WM, Chin L, Picchioni AL. Enhancement of audiogenic seizure by 6-hydroxydopamine. J Pharm Pharmacol 24: 913–914, 1972.
Ungerstedt U. 6-Hydroxydopamine induced degeneration of central monoamine neurons. Eur J Pharmacol 5: 107–110, 1968.
Ungerstedt U. Stereotaxic mapping of the monoamine pathways in the rat brain. Acta Physiol Scand Suppl 367: 1–48, 1971.
Javoy F, Sotelo C, Herbert A, Agid Y. Specificity of dopaminergic neuronal degeneration induced by intracerebral injection of 6-hydroxydopamine in the nigrostriatal dopamine system. Brain Res 102: 210–215, 1976.
Jeon BS, Jackson-Lewis V, Burke RE. 6-Hydroxydopamine lesion of the rat substantia nigra: time course and morphology of cell death. Neurodegeneration 4: 131–137, 1995.
Faull RL, Laverty R. Changes in dopamine levels in the corpus striatum following lesions in the substantia nigra. Exp Neurol 23: 332–340, 1969.
Sane S, Yuan H, Jonkers N, Van HA, Ebinger G, Michotte Y. In vivo characterization of somatodendritic dopamine release in the substantia nigra of 6-hydroxydopamine-lesioned rats. J Neurochem 90: 29–39, 2004.
Przedborski S, Levivier M, Jiang H, Ferreira M, Jackson-Lewis V, Donaldson D, et al. Dose-dependent lesions of the dopaminergic nigrostriatal pathway induced by intrastriatal injection of 6-hydroxydopamine. Neuroscience 67: 631–647, 1995.
Sauer H, Oertel WH. Progressive degeneration of nigrostriatal dopamine neurons following intrastriatal terminal lesions with 6-hydroxydopamine: a combined retrograde tracing and immunocytochemical study in the rat. Neuroscience 59: 401–415, 1994.
Marti MJ, James CJ, Oo TF, Kelly WJ, Burke RE. Early developmental destruction of terminals in the striatal target induces apoptosis in dopamine neurons of the substantia nigra. J Neurosci 17: 2030–2039, 1997.
Stromberg I, Bjorklund H, Dahl D, Jonsson G, Sundstrom E, Olson L. Astrocyte responses to dopaminergic denervations by 6-hydroxydopamine and l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine as evidenced by glial fibrillary acidic protein immunohistochemistry. Brain Res Bull 17: 225–236, 1986.
Saura J, Pares M, Bove J, Pezzi S, Alberch J, Marin C, et al. Intranigral infusion of interleukin-lβ activates astrocytes and protects from subsequent 6-hydroxydopamine neurotoxicity. J Neurochem 85: 651–661, 2003.
Rodriguez DM, Abdala P, Barroso-Chinea P, Obeso J, Gonzalez-Hemandez T. Motor behavioural changes after intracerebroventricular injection of 6-hydroxydopamine in the rat: an animal model of Parkinson’s disease. Behav Brain Res 122: 79–92, 2001.
Cenci MA, Whishaw IQ, Schallert T. Animal models of neurological deficits: how relevant is the rat? Nat Rev Neurosci 3: 574–579, 2002.
Ungerstedt U, Arbuthnott G. Quantitative recording of rotational behaviour in rats after 6-hydroxydopamine lesions of the nigrostriatal dopamine system. Brain Res 24: 485–493, 1970.
Hefti F, Melamed E, Wurtman RJ. Partial lesions of the dopaminergic nigrostriatal system in rat brain: biochemical characterization. Brain Res 195: 123–137, 1980.
Jiang H, Jackson-Lewis V, Muthane U, Dollison A, Ferreira M, Espinosa A, et al. Adenosine receptor antagonists potentiate dopamine receptor agonist-induced rotational behavior in 6-hydroxydopamine-lesioned rats. Brain Res 613: 347–351, 1993.
Kirik D, Georgievska B, Burger C, Winkler C, Muzyczka N, Mandel RJ, et al. Reversal of motor impairments in parkinsonian rats by continuous intrastriatal delivery of L-dopa using rAAV-mediated gene transfer. Proc Natl Acad Sci USA 99: 4708–4713, 2002.
Bjorklund LM, Sanchez-Pemaute R, Chung S, Andersson T, Chen IY, McNaught KS, et al. Embryonic stem cells develop into functional dopaminergic neurons after transplantation in a Parkinson rat model. Proc Natl Acad Sci USA 99: 2344–2349, 2002.
Papa SM, Engber TM, Kask AM, Chase TN. Motor fluctuations in levodopa treated parkinsonian rats: relation to lesion extent and treatment duration. Brain Res 662: 69–74, 1994.
Bove J, Marin C, Bonastre M, Tolosa E. Adenosine A2A antagonism reverses levodopa-induced motor alterations in hemiparkinsonian rats. Synapse 46: 251–257, 2002.
Olsson M, Nikkhah G, Bentlage C, Bjorklund A. Forelimb akinesia in the rat Parkinson model: differential effects of dopamine agonists and nigral transplants as assessed by a new stepping test. J Neurosci 15: 3863–3875, 1995.
Hoglinger GU, Rizk P, Muriel MP, Duyckaerts C, Oertel WH, Caille I, et al. Dopamine depletion impairs precursor cell proliferation in Parkinson disease. Nat Neurosci 7: 726–735, 2004.
Frielingsdorf H, Schwarz K, Brundin P, Mohapel P. No evidence for new dopaminergic neurons in the adult mammalian substantia nigra. Proc Natl Acad Sci USA 101: 10177–10182, 2004.
Aebischer P, Tresco PA, Sagen J, Winn SR. Transplantation of microencapsulated bovine chromaffin cells reduces lesion-induced rotational asymmetry in rats. Brain Res 560: 43–49, 1991.
Bal A, Savasta M, Chritin M, Mennicken F, Abrous DN, Le Moal M, et al. Transplantation of fetal nigral cells reverses the increase of preproenkephalin mRNA levels in the rat striatum caused by 6-OHDA lesion of the dopaminergic nigrostriatal pathway: a quantitative in situ hybridization study. Mol Brain Res 18: 221–227, 1993.
Venero JL, Beck KD, Hefti F. 6-Hydroxydopamine lesions reduce BDNF mRNA levels in adult rat brain substantia nigra. Neuroreport 5: 429–432, 1994.
St-Pierre JA, Bédard PJ. Intranigral but not intrastriatal microinjection of the NMDA antagonist MK-801 induces contralateral circling in the 6-OHDA rat model. Brain Res 660: 255–260, 1994.
Kearns CM, Cass WA, Smoot K, Kryscio R, Gash DM. GDNF protection against 6-OHDA: time dependence and requirement for protein synthesis. J Neurosci 17: 7111–7118, 1997.
Nakao N, Nakai E, Nakai K, Itakura T. Ablation of the subthalamic nucleus supports the survival of nigral dopaminergic neurons after nigrostriatal lesions induced by the mitochondrial toxin 3-nitropropionic acid. Ann Neurol 45: 640–651, 1999.
Chen L, Liu Z, Tian Z, Wang Y, Li S. Prevention of neurotoxin damage of 6-OHDA to dopaminergic nigral neuron by subthalamic nucleus lesions. Stereotact Funct Neurosurg 75: 66–75, 2000.
Maesawa S, Kaneoke Y, Kajita Y, Usui N, Misawa N, Nakayama A, et al. Long-term stimulation of the subthalamic nucleus in hemiparkinsonian rats: neuroprotection of dopaminergic neurons. J Neurosurg 100: 679–687, 2004.
Trugman JM, Wooten GF. Selective D1 and D2 dopamine agonists differentially alter basal ganglia glucose utilization in rats with unilateral 6-hydroxydopamine substantia nigra lesions. J Neurosci 7: 2927–2935, 1987.
Gerfen CR, Baimbridge KG, Miller JJ. The neostriatal mosaic: Comparmental distribution of calcium-binding protein and parvalbumin in the basal ganglia of the rat and monkey. Proc Natl Acad Sci USA 82: 8780–8784, 1985.
Gerfen CR, Baimbridge KG, Thibault J. The neostriatal mosaic: III. Biochemical and developmental dissociation of patch-matrix nigrostriatal system. J Neurosci 7: 3935–3944, 1987.
Gerfen CR, Herkenham M, Thibault J. The neostriatal mosaic: II. Patch- and matrix-directed mesostriatal dopaminergic and non-dopaminergic systems. J Neurosci 7: 3915–3934, 1987.
Gerfen CR, Engber TM, Mahan LC, Susel Z, Chase TN, Monsma FJ, et al. D1 and D2 dopamine receptor-regulated gene expression of striatonigral and striatopallidal neurons. Science 250: 1429–1432, 1990.
Blum D, Torch S, Lambeng N, Nissou M, Benabid AL, Sadoul R, et al. Molecular pathways involved in the neurotoxicity of 6-OHDA, dopamine and MPTP: contribution to the apoptotic theory in Parkinson’s disease. Prog Neurobiol 65: 135–172, 2001.
Langsten JW, Ballard P, Irwin I. Chronic parkinsonism in humans due to a product of meperidine-analog synthesis. Science 219: 979–980, 1983.
Kopin IJ. MPTP: an industrial chemical and contaminant of illicit narcotics stimulates a new era in research on Parkinson’s disease. Environ Health Perspect 75: 45–51, 1987.
Kitamura Y, Kakimura J, Taniguchi T. Protective effect of talipexole on MPTP-treated planarian, a unique parkinsonian worm model. Jpn J Pharmacol 78: 23–29, 1998.
Przedborski S, Jackson-Lewis V, Naini A, Jakowec M, Petzinger G, Miller R, et al. The parkinsonian toxin l-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP): a technical review of its utility and safety. J Neurochem 76: 1265–1274, 2001.
Przedborski S, Vila M. MPTP: a review of its mechanisms of neurotoxicity. Clin Neurosci Res 1: 407–418, 2001.
Tetrud JW, Langsten JW, Redmond DE Jr, Roth RH, Sladek JR, Angel RW. MPTP-induced tremor in human and non-human primates. Neurology 36(Suppl 1): 308, 1986.
Stem Y. MPTP-induced parkinsonism. Prog Neurobiol 34: 107–114, 1990.
Stem Y, Tetrud JW, Martin WR, Kutner SJ, Langsten JW. Cognitive change following MPTP exposure. Neurology 40: 261–264, 1990.
Decamp E, Schneider JS. Attention and executive function deficits in chronic low-dose MPTP-treated non-human primates. Eur J Neurosci 20: 1371–1378, 2004.
Kostic V, Przedborski S, Flaster E, Stemic N. Early development of levodopa-induced dyskinesias and response fluctuations in young-onset Parkinson’s disease. Neurology 41: 202–205, 1991.
Langsten JW, Ballard P. Parkinsonism induced by l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP): implications for treatment and the pathogenesis of Parkinson’s disease. Can J Neurol Sci 11: 160–165, 1984.
Blanchet PJ, Calon F, Morissette M, Tahar AH, Belanger N, Samadi P, et al. Relevance of the MPTP primate model in the study of dyskinesia priming mechanisms. Parkinsonism Relat Disord 10: 297–304, 2004.
Bézard E, Ferry S, Mach U, Stark H, Leriche L, Boraud T, et al. Attenuation of levodopa-induced dyskinesia by normalizing dopamine D3 receptor function. Nat Med 9: 762–767, 2003.
Davis GC, Williams AC, Markey SP, Ebert MH, Caine ED, Reichert CM, et al. Chronic parkinsonism secondary to intravenous injection of meperidine analogs. Psychiatry Res 1: 249–254, 1979.
Fomo LS, DeLanney LE, Irwin I, Langston JW. Similarities and differences between MPTP-induced parkinsonism and Parkinson’s disease: Neuropathologic considerations. Adv Neurol 60: 600–608, 1993.
Agid Y, Javoy-Agid F, Ruberg M. Biochemistry of neurotransmitters in Parkinson’s disease. In: Movement disorders 2 (Marsden CD, Fahn S, eds), pp 166–230. London: Butterworths, 1987.
Seniuk NA, Tatton WG, Greenwood CE. Dose-dependent destruction of the coeruleus-cortical and nigral-striatal projections by MPTP. Brain Res 527: 7–20, 1990.
Muthane U, Ramsay KA, Jiang H, Jackson-Lewis V, Donaldson D, Fernando S, et al. Differences in nigral neuron number and sensitivity to 1-methyl-4-phenyl-l,2,3,6-tetrahydropyridine in C57/bl and CD-1mice. Exp Neurol 126: 195–204, 1994.
Moratalla R, Quinn B, DeLanney LE, Irwin I, Langston JW, Graybiel AM. Differential vulnerability of primate caudate-putamen and striosome-matrix dopamine systems to the neurotoxic effects of 1-methyl-4-phenyl-l,2,3,6-tetrahydropyridine. Proc Natl Acad Sci USA 89: 3859–3863, 1992.
Snow BJ, Vingerhoets FJ, Langston JW, Tetrud JW, Sossi V, Calne DB. Pattern of dopaminergic loss in the striatum of humans with MPTP induced parkinsonism. J Neurol Neurosurg Psychiat 68: 313–316, 2000.
Fomo LS, Langston JW, DeLanney LE, Irwin I, Ricaurte GA. Locus ceruleus lesions and eosinophilic inclusions in MPTP-treated monkeys. Ann Neurol 20: 449–455, 1986.
Burns RS, Pakkenberg H, Kopin IJ. Lack of progression of MPTP-induced parkinsonism during long-term treatment with L-DOPA. Ann Neurol 18: 117, 1985.
Vingerhoets FJ, Snow BJ, Tetrud JW, Langston JW, Schulzer M, Calne DB. Positron emission tomographic evidence for progression of human MPTP-induced dopaminergic lesions. Ann Neurol 36: 765–770, 1994.
Langston JW, Forno LS, Tetrud J, Reeves AG, Kaplan JA, Karluk D. Evidence of active nerve cell degeneration in the substantia nigra of humans years after l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine exposure. Ann Neurol 46: 598–605, 1999.
McGeer PL, Schwab C, Parent A, Doudet D. Presence of reactive microglia in monkey substantia nigra years after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine administration. Ann Neurol 54: 599–604, 2003.
Bergman H, Wichmann T, DeLong MR. Reversal of experimental parkinsonism by lesions of the subthalamic nucleus. Science 249: 1436–1438, 1990.
Limousin P, Krack P, Pollak P, Benazzouz A, Ardouin C, Hoffmann D, et al. Electrical stimulation of the subthalamic nucleus in advanced Parkinson’s disease. N Engl J Med 339: 1105–1111, 1998.
Gash DM, Zhang ZM, Ovadia A, Cass WA, Yi A, Simmerman L, et al. Functional recovery in parkinsonian monkeys treated with GDNF. Nature 380: 252–255, 1996.
Kordower JH, Emborg ME, Bloch J, Ma SY, Chu Y, Leventhal L, et al. Neurodegeneration prevented by lentiviral vector delivery of GDNF in primate models of Parkinson’s disease. Science 290: 767–773, 2000.
Betarbet R, Sherer TB, MacKenzie G, Garcia-Osuna M, Panov AV, Greenamyre JT. Chronic systemic pesticide exposure reproduces features of Parkinson’s disease. Nat Neurosci 3: 1301–1306, 2000.
Hisata J. Final supplemental environmental impact statement. Lake and stream rehabilitation: rotenone use and health risks. Washington State Department of Fish and Wildlife, 2002.
Butterfield PG, Valanis BG, Spencer PS, Lindeman CA, Nutt JG. Environmental antecedents of young-onset Parkinson’s disease. Neurology 43: 1150–1158, 1993.
Gorell JM, Johnson CC, Rybicki BA, Peterson EL, Richardson RJ. The risk of Parkinson’s disease with exposure to pesticides, farming, well water, and rural living. Neurology 50: 1346–1350, 1998.
Marking L. Oral toxicity of rotenone to mammals. Investig Fish Control, Issue No. 94, 1988.
De Wilde AR, Heyndrickx A, Carton D. A case of fatal rotenone poisoning in a child. J Forensic Sci 31: 1492–1498, 1986.
Talpade DJ, Greene JG, Higgins DS Jr, Greenamyre JT. In vivo labeling of mitochondrial complex I (NADH:ubiquinone oxidoreductase) in rat brain using [(3)H]dihydrorotenone. J Neurochem 75: 2611–2621, 2000.
Schuler F, Casida JE. Functional coupling of PSST and ND1 subunits in NADH:ubiquinone oxidoreductase established by photoaffinity labeling. Biochim Biophys Acta 1506: 79–87, 2001.
Marshall LE, Himes RH. Rotenone inhibition of tubulin self-assembly. Biochim Biophys Acta 543: 590–594, 1978.
Brinkley BR, Barham SS, Barranco SC, Fuller GM. Rotenone inhibition of spindle microtubule assembly in mammalian cells. Exp Cell Res 85: 41–46, 1974.
Burke D, Gasdaska P, Hartwell L. Dominant effects of tubulin overexpression in Saccharomyces cerevisiae. Mol Cell Biol 9: 1049–1059, 1989.
Weinstein B, Solomon F. Phenotypic consequences of tubulin overproduction in Saccharomyces cerevisiae: differences between α-tubulin and β-tubulin. Mol Cell Biol 10: 5295–5304, 1990.
Ren Y, Zhao J, Feng J. Parkin binds to α/β tubulin and increases their ubiquitination and degradation. J Neurosci 23: 3316–3324, 2003.
Marey-Semper I, Gelman M, Lévi-Strauss M. A selective toxicity toward cultured mesencephalic dopaminergic neurons is induced by the synergistic effects of energetic metabolism impairment and NMDA receptor activation. J Neurosci 15: 5912–5918, 1995.
Gao HM, Hong JS, Zhang W, Liu B. Distinct role for microglia in rotenone-induced degeneration of dopaminergic neurons. J Neurosci 22: 782–790, 2002.
Heikkila RE, Nicklas WJ, Vyas I, Duvoisin RC. Dopaminergic toxicity of rotenone and the l-methyl-4-phenylpyridinium ion after their stereotaxic administration to rats: implication for the mechanism of l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine toxicity. Neurosci Lett 62: 389–394, 1985.
Fen-ante RJ, Schulz JB, Kowall NW, Beal MF. Systemic administration of rotenone produces selective damage in the striatum and globus pallidus, but not in the substantia nigra. Brain Res 753: 157–162, 1997.
Thiffault C, Langston JW, Di Monte DA. Increased striatal dopamine turnover following acute administration of rotenone to mice. Brain Res 885: 283–288, 2000.
Sherer TB, Kim JH, Betarbet R, Greenamyre JT. Subcutaneous rotenone exposure causes highly selective dopaminergic degeneration and a-synuclein aggregation. Exp Neurol 179: 9–16, 2003.
Hoglinger GU, Feger J, Annick P, Michel PP, Karine P, Champy P, et al. Chronic systemic complex I inhibition induces a hypokinetic multisystem degeneration in rats. J Neurochem 84: 1–12, 2003.
Lapointe N, St-Hilaire M, Martinoli MG, Blanchet J, Gould P, Rouillard C, et al. Rotenone induces non-specific central nervous system and systemic toxicity. FASEB J 18: 717–719, 2004.
Zhu C, Vourc’h P, Femagut PO, Fleming SM, Lacan S, Dicarlo CD, et al. Variable effects of chronic subcutaneous administration of rotenone on striatal histology. J Comp Neurol 478: 418–426, 2004.
Alam M, Schmidt WJ. Rotenone destroys dopaminergic neurons and induces parkinsonian symptoms in rats. Behav Brain Res 136: 317–324, 2002.
Alam M, Mayerhofer A, Schmidt WJ. The neurobehavioral changes induced by bilateral rotenone lesion in medial forebrain bundle of rats are reversed by L-DOPA. Behav Brain Res 151: 117–124, 2004.
Fleming SM, Zhu C, Femagut PO, Mehta A, Dicarlo CD, Seaman RL, et al. Behavioral and immunohistochemical effects of chronic intravenous and subcutaneous infusions of varying doses of rotenone. Exp Neurol 187: 418–429, 2004.
Day BJ, Patel M, Calavetta L, Chang LY, Stamler JS. A mechanism of paraquat toxicity involving nitric oxide synthase. Proc Natl Acad Sci USA 96: 12760–12765, 1999.
Smith JG. Paraquat poisoning by skin absorption: a review. Hum Toxicol 7: 15–19, 1988.
Grant H, Lantos PL, Parkinson C. Cerebral damage in paraquat poisoning. Histopathology 4: 185–195, 1980.
Hughes JT. Brain damage due to paraquat poisoning: a fatal case with neuropathological examination of the brain. Neurotoxicology 9: 243–248, 1988.
Shimizu K, Ohtaki K, Matsubara K, Aoyama K, Uezono T, Saito O, et al. Carrier-mediated processes in blood-brain barrier penetration and neural uptake of paraquat. Brain Res 906: 135–142, 2001.
Liou HH, Tsai MC, Chen CJ, Jeng JS, Chang YC, Chen SY, et al. Environmental risk factors and Parkinson’s disease: a case-control study in Taiwan. Neurology 48: 1583–1588, 1997.
Brooks AI, Chadwick CA, Gelbard HA, Cory-Slechta DA, Federoff HJ. Paraquat elicited neurobehavioral syndrome caused by dopaminergic neuron loss. Brain Res 823: 1–10, 1999.
McCormack AL, Di Monte DA. Effects of L-dopa and other amino acids against paraquat-induced nigrostriatal degeneration. J Neurochem 85: 82–86, 2003.
Thiruchelvam M, Brockel BJ, Richfield EK, Baggs RB, Cory-Slechta DA. Potentiated and preferential effects of combined paraquat and maneb on nigrostriatal dopamine systems: environmental risk factors for Parkinson’s disease? Brain Res 873: 225–234, 2000.
Thiruchelvam M, Richfield EK, Baggs RB, Tank AW, Cory-Slechta DA. The nigrostriatal dopaminergic system as a preferential target of repeated exposures to combined paraquat and maneb: implications for Parkinson’s disease. J Neurosci 20: 9207–9214, 2000.
McCormack AL, Thiruchelvam M, Manning-Bog AB, Thiffault C, Langston JW, Cory-Slechta DA, et al. Environmental risk factors and Parkinson’s disease: selective degeneration of nigral dopaminergic neurons caused by the herbicide paraquat. Neurobiol Dis 10: 119–127, 2002.
Manning-Bog AB, McCormack AL, Li J, Uversky VN, Fink AL, Di Monte DA. The herbicide paraquat causes up-regulation and aggregation of alpha-synuclein in mice: paraquat and α-synuclein. J Biol Chem 277: 1641–1644, 2002.
Manning-Bog AB, McCormack AL, Purisai MG, Bolin LM, Di Monte DA. α-Synuclein overexpression protects against paraquat-induced neurodegeneration. J Neurosci 23: 3095–3099, 2003.
Singleton AB, Faner M, Johnson J, Singleton A, Hague S, Kachergus J, et al. α-Synuclein locus triplication causes Parkinson’s disease. Science 302: 841, 2003.
Peng J, Mao XO, Stevenson FF, Hsu M, Andersen JK. The herbicide paraquat induces dopaminergic nigral apoptosis through sustained activation of the JNK pathway. J Biol Chem 279: 32626–32632, 2004.
Thiiuchelvam M, Richfield EK, Goodman BM, Baggs RB, Cory-Slechta DA. Developmental exposure to the pesticides paraquat and maneb and the Parkinson’s disease phenotype. Neurotoxicology 23: 621–633, 2002.
Barlow BK, Richfield EK, Cory-Slechta DA, Thiruchelvam M. A fetal risk factor for Parkinson’s disease. Dev Neurosci 26: 11–23, 2004.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Bové, J., Prou, D., Perier, C. et al. Toxin-induced models of Parkinson’s disease. Neurotherapeutics 2, 484–494 (2005). https://doi.org/10.1602/neurorx.2.3.484
Issue Date:
DOI: https://doi.org/10.1602/neurorx.2.3.484