• MOHD IMRAN Department of , Faculty of Pharmacy, Integral University, Disable, Kursi Road, Lucknow, India.
  • ANURADHA MISHRA Department of , Faculty of Pharmacy, Integral University, Disable, Kursi Road, Lucknow, India.
  • AFREEN USMANI Department of , Faculty of Pharmacy, Integral University, Disable, Kursi Road, Lucknow, India.
  • ASIF EQBAL Department of , Faculty of Pharmacy, Integral University, Disable, Kursi Road, Lucknow, India.




Nil, Neurodegenerative, Experimental models, Neurotoxin


Parkinson’s disease (PD) is the 2nd most common neurodegenerative disorder due to gradual loss of dopaminergic nerves in the substantia nigra in the midbrain which leads to motor symptoms: For instance, gait dysfunction, involuntary tremor, rigidity, and progressive postural instability. PD has no cure and available current treatment is only symptomatic. At present, the main treatment of PD relies on Levodopa that slowing down the disease development to some level but can lead to several side effects. The literature confirms the available models of Parkinsonism that is chemical-induced, that is, by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and 6-hydroxydopamine-induced Parkinsonism furthermore transgenic models linked to monogenic alterations in SNCA, LRRK2, UCH-L1, PRKN, and PINK1 genes. In this review article, we conclude that the presently available neurotoxic models of PD that offer a platform for neuroprotective drug discovery.


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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 2000;3:1301-6.

Gibb WR, Lees AJ. The relevance of the Lewy body to the pathogenesis of idiopathic Parkinson’s disease. J Neurol Neurosurg Psychiatry 1988;51:745-52.

Arvid C, Lindqvist M, Magnusson TO. 3,4-dihydroxyphenylalanine and 5-hydroxytryptophan as reserpine antagonists. Nature 1957;180:1200.

William D, Przedborski S. Parkinson’s disease: Mechanisms and models. Neuron 2003;39:889-909.

Angela CM, Whishaw IQ, Schallert T. Animal models of neurological deficits: How relevant is the rat? Nat Rev Neurosci 2002;3:574-9.

Blandini F, Levandis G, Bazzini E, Nappi G, Armentero MT. Time-course of nigrostriatal damage, basal ganglia metabolic changes and behavioural alterations following intrastriatal injection of 6-hydroxydopamine in the rat: New clues from an old model. Eur J Neurosci 2007;25:397-405.

Dauer W, Przedborski S. Parkinson’s disease: Mechanisms and models. Neuron 2003;39:889-909.

Rivlin-Etzion M, Elias S, Heimer G, Bergman H. Computational physiology of the basal ganglia in Parkinson’s disease. In: Progress in Brain Research. Vol. 183. Netherlands: Elsevier; 2010. p. 259-73.

Chiueh CC, Markey SP, Burns RS, Johannessen JN, Jacobowitz DM, Kopin IJ. Neurochemical and behavioral effects of 1-methyl-4- phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) in rat, guinea pig, and monkey. Psychopharmacol Bull 1984;20:548-53.

Jackson-Lewis V, Przedborski S. Protocol for the MPTP mouse model of Parkinson’s disease. Nat Protoc 2007;2:141.

Meredith GE, Totterdell S, Potashkin JA, Surmeier DJ. Modellering PD pathogenese bij muizen: Voordelen van een chronisch MPTP-protocol. Parkinsonisme Relat Disord 2008;14:S112-5.

Bezard E, Imbert C, Deloire X, Bioulac B, Gross CE. A chronic MPTP model reproducing the slow evolution of Parkinson’s disease: Evolution of motor symptoms in the monkey. Brain Res 1997;766:107-12.

Blesa J, Pifl C, Sánchez-González MA, Juri C, García-Cabezas MA, Adánez R, et al. The nigrostriatal system in the presymptomatic and symptomatic stages in the MPTP monkey model: A PET, histological and biochemical study. Neurobiol Dis 2012;48:79-91.

Porras G, Li Q, Bezard E. Modeling Parkinson’s disease in primates: The MPTP model. Cold Spring Harb Persp Med 2012;2:a009308.

Langston JW, Ballard PA Jr. Parkinson’s disease in a chemist working with l-methyl-4-phenyl-l, 2, 5, 6-tetrahydropyridine. N Engl J Med 1983;309:310.

Davis GC, Williams AC, Markey SP, Ebert MH, Caine ED, Reichert CM, et al. Chronic parkinsonism secondary to intravenous injection of meperidine analogues. Psychiatry Res 1979;1:249-54.

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 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine exposure. Ann Neurol 1999;46:598-605.

Beal MF. Mitochondria, oxidative damage, and inflammation in Parkinson’s disease. Ann N Y Acad Sci 2003;991:120-31.

Przedborski S, Vila A. A tool to explore the pathogenesis of Parkinson’s disease. Doc Page 2003;991:189-98.

Nicklas WJ, Vyas I, Heikkila RE. 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 1985;36:2503-8.

Geng X, Tian X, Tu P, Pu X. Neuroprotective effects of echinacoside in the mouse MPTP model of Parkinson’s disease. Eur J Pharmacol 2007;564:66-74.

Kim HG, Ju MS, Shim JS, Kim MC, Lee SH, Huh Y, et al. Mulberry fruit protects dopaminergic neurons in toxin-induced Parkinson’s disease models. Br J Nutr 2010;104:8-16.

Blum D, Torch S, Lambeng N, Nissou MF, 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 2001;65:135-72.

Senoh S, Witkop B. Non-enzymatic conversions of dopamine to norepinephrine and trihydroxyphenethylamines1. J Am Chem Soc 1959;81:6222-31.

Porter CC, Totaro JA, Stone CA. Effect of 6-hydroxydopamine and some other compounds on the concentration of norepinephrine in the hearts of mice. J Pharmacol Exp Ther 1963;140:308-16.

Porter CC, Totaro JA, Burcin A. The relationship between radioactivity and norepinephrine concentrations in the brains and hearts of mice following administration of labeled methyldopa or 6-hydroxydopamine. J Pharmacol Exp Ther 1965;150:17-22.

Sachs C, Jonsson G. Mechanisms of action of 6-hydroxydopamine. Biochem Pharmacol 1975;24:1-8.

Ungerstedt U. 6-Hydroxy-dopamine induced degeneration of central monoamine neurons. Eur J Pharmacol 1968;5:107-10.

Ungerstedt U. 6-hydroxydopamine-induced degeneration of the nigrostriatal dopamine pathway: The turning syndrome. Pharmacol Ther B 1976;2:37-40.

Luthman J, Fredriksson A, Sundström E, Jonsson G, Archer T. Selective lesion of central dopamine or noradrenaline neuron systems in the neonatal rat: Motor behavior and monoamine alterations at adult stage. Behav Brain Res 1989;33:267-77.

Jeon BS, Jackson-Lewis V, Burke RE. 6-hydroxydopamine lesion of the rat substantia nigra: Time course and morphology of cell death. Neurodegeneration 1995;4:131-7.

Thoenen H, Tranzer JP. Chemical sympathectomy by selective destruction of adrenergic nerve endings with 6-hydroxydopamine. Naunyn Schmiedebergs Arch Für Pharmakol Exp Pathol 1968;261:271-88.

Tranzer JP, Thoenen H. An electron microscopic study of selective, acute degeneration of sympathetic nerve terminals after administration of 6-hydroxydopamine. Experientia 1968;24:155-6.

Unsicker K, Allan IJ, Newgreen DF. Extraneuronal effects of 6-hydroxydopamine and extraneuronal uptake of noradrenaline. Cell Tissue Res 1976;173:45-69.

Thoenen H. Surgical, immunological and chemical sympathectomy their application in the investigation of the physiology and pharmacology of the sympathetic nervous system. In: Catecholamines.Berlin, Heidelberg: Springer; 1972. p. 813-44.

Perese DA, Ulman J, Viola J, Ewing SE, Bankiewicz KS. A 6-hydroxydopamine-induced selective parkinsonian rat model. Brain Res 1989;494:285-93.

Przedbroski S, Leviver M, Jiang H, Ferreira M, Jackson-Lewis V, Donaldson D, et al. Dose-dependent lesions of the dopaminergic nigrostriatal pathway induced by instrastriatal injection of 6-hydroxydopamine. Neuroscience 1995;67:631-47.

Esposti DM. Inhibitors of NADH-ubiquinone reductase: An overview. Biochim Biophys Acta 1998;1364:222-35.

Talpade DJ, Greene JG, Higgins DS Jr., Greenamyre JT. In vivo labeling of mitochondrial complex i (NADH:Ubiquinone oxidoreductase) in rat brain using [3h] dihydrorotenone. J Neurochem 2000;75:2611-21.

Davey GP, Clark JB. Threshold effects and control of oxidative phosphorylation in nonsynaptic rat brain mitochondria. J Neurochem 1996;66:1617-24.

Higgins DS Jr., Greenamyre JT. [3H] dihydrorotenone binding to NADH: Ubiquinone reductase (complex I) of the electron transport chain: An autoradiographic study. J Neurosci 1996;16:3807-16.

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 2000;3:1301-6.

Sherer, TB, Kim JH, Betarbet R, Greenamyre JT. Subcutaneous rotenone exposure causes highly selective dopaminergic degeneration and α-synuclein aggregation. Exp Neurol 2003;179:9-16.

Fleming SM, Zhu C, Fernagut 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 2004;187:418-29.

Pan-Montojo F, Anichtchik O, Dening Y, Knells L, Pursche S, Jung R, et al. Progression of Parkinson’s disease pathology is reproduced by intragastric administration of rotenone in mice. Nat Prec 2009;29:1480-5.

Caudle WM, Colebrooke RE, Emson PC, Miller GW. Altered vesicular dopamine storage in Parkinson’s disease: A premature demise. Trends Neurosci 2008;31:303-8.

Tsang AH, Chung KK. Oxidative and nitrosative stress in Parkinson’s disease. Biochim Biophys Acta 2009;1792:643-50.

Lohr JB. Oxygen radicals and neuropsychiatric illness: Some speculations. Arch Gene Psychiatry 1991;48:1097-106.

Droge W. Free radicals in the physiological control of cell function. Physiol Rev 2002;82:47-95.

Hornykiewicz O. Die topische lokalization und des verhalten von noradrenalin und dopamin (3-hydroxytyramin) in der substantia nigra der normalen und Parkinson kranken Menschen. Wien Klin Wochschr 1963;75:309-12.

Bernheimer H, Birkmayer W, Hornykiewicz O, Jellinger K, Seitelberger F. Brain dopamine and the syndromes of Parkinson and Huntington clinical, morphological and neurochemical correlations. J Neurol Sci 1973;20:415-55.

Hornykiewicz O. Dopamine (3-hydroxytyramine) and brain function. Pharmacol Rev 1966;18:925-64.

Lücking CB, Dürr A, Bonifati V, Vaughan J, De Michele G, Gasser T, et al, The French Parkinson’s Disease Genetics Study Group; European Consortium on Genetic Susceptibility in Parkinson’s Disease. Association between early-onset Parkinson’s disease and mutations in the parkingene. N Engl J Med 2000;342:1560-7.

Periquet M, Latouche M, Lohmann E, Rawal N, De Michele G, Ricard S, et al. Parkin mutations are frequent in patients with isolated early-onset parkinsonism. Brain 2003;126:1271-8.

Goldberg MS, Fleming SM, Palacino JJ, Cepeda C, Lam HA, Bhatnagar A, et al. Parkin-deficient mice exhibit nigrostriatal deficits but not loss of dopaminergic neurons. J Biol Chem 2003;278:43628-35.

Jean-Michel I, Ibáñez P, Mena MA, Abbas N, Cohen-Salmon C, Bohme GA, et al. Parkin gene inactivation alters behaviour and dopamine neurotransmission in the mouse. Hum Mol Genet 2003;12:2277-91.

Palacino JJ, Sagi D, Goldberg MS, Krauss S, Motz C, Wacker M, et al. Mitochondrial dysfunction and oxidative damage in parkin-deficient mice. J Biol Chem 2004;279:18614-22.

Perez FA, Palmiter RD. Parkin-deficient mice are not a robust model of parkinsonism. Proc Natl Acad Sci 2005;102:2174-9.

Xin-Ran Z, Maskri L, Herold C, Bader V, Stichel CC, Güntürkün O, et al. Non-motor behavioural impairments in parkin-deficient mice. Eur J Neurosci 2007;26:1902-11.

Martella G, Platania P, Vita D, Sciamanna G, Cuomo D, Tassone A, et al. Enhanced sensitivity to Group II mGlu receptor activation at corticostriatal synapses in mice lacking the familial parkinsonism-linked genes PINK1 or Parkin. Exp Neurol 2009;215:388-96.

Kitada T, Pisani A, Porter DR, Yamaguchi H, Tscherter A, Martella G, et al. Impaired dopamine release and synaptic plasticity in the striatum of PINK1-deficient mice. Proc Natl Acad Sci 2007;104:11441-6.

Xiao-Hong L, Fleming SM, Meurers B, Ackerson LC, Mortazavi F, Lo V, et al. Bacterial artificial chromosome transgenic mice expressing a truncated mutant parkin exhibit age-dependent hypokinetic motor deficits, dopaminergic neuron degeneration, and accumulation of proteinase K-resistant α-synuclein. J Neurosci 2009;29:1962-76.

Van Rompuy AS, Lobbestael E, Van der Perren A, Van den Haute C, Baekelandt V. Long-term overexpression of human wild-type and T240R mutant parkin in rat substantia nigra induces progressive dopaminergic neurodegeneration. J Neuropathol Exp Neurol 2014;73:159-74.

Fujikawa T, Shinji M, Kanada N, Nakai N, Ogata M, Suzuki I, et al. Acanthopanax senticosus harms as a prophylactic for MPTP-induced Parkinson’s disease in rats. J Ethnopharmacol 2005;97:375-81.

Patricia R, Serrano-García N, Medina-Campos ON, Pedraza-Chaverri J, Maldonado PD, Ruiz-Sánchez E. S-allylcysteine, a garlic compound, protects against oxidative stress in 1-methyl-4-phenylpyridinium-induced parkinsonism in mice. J Nutr Biochem 2011;22:937-44.

Radad K, Gille G, Moldzio R, Saito H, Ishige K, Rausch WD. Ginsenosides Rb1 and Rg1 effects on survival and neurite growth of MPP+-affected mesencephalic dopaminergic cells. J Neural Transm 2004;111:37-45.

Chen J, Tang XQ, Zhi JL, Cui Y, Yu HM, Tang EH, et al. Curcumin protects PC12 cells against 1-methyl-4-phenylpyridinium ion-induced apoptosis by bcl-2-mitochondria-ROS-iNOS pathway. Apoptosis 2006;11:943-53.

Kim IS, Choi DK, Jung HJ. Neuroprotective effects of vanillyl alcohol in Gastrodia elata blume through suppression of oxidative stress and anti-apoptotic activity in toxin-induced dopaminergic MN9D cells. Molecules 2011;16:5349-61.

Kai Z, Ma Z, Wang J, Xie A, Xie JX. Myricetin attenuated MPP+-induced cytotoxicity by anti-oxidation and inhibition of MKK4 and JNK activation in MES23. 5 cells. Neuropharmacology 2011;61:329-35.

Yamaratee J, Thampithak A, Meesarapee B, Ratanachamnong P, Suksamrarn A, Phivthong-Ngam L, et al. Curcumin I protects the dopaminergic cell line SH-SY5Y from 6-hydroxydopamine-induced neurotoxicity through attenuation of p53-mediated apoptosis. Neurosci Lett 2011;489:192-6.

Ye-Ming L, Jiang B, Bao YM, An LJ. Protocatechuic acid inhibits apoptosis by mitochondrial dysfunction in rotenone-induced PC12 cells. Toxicol in Vitro 2008;22:430-7.

Molina-Jiménez, Francisca M, Sánchez-Reus MI, Cascales M, Andrés D, Benedí J. Effect of fraxetin on antioxidant defense and stress proteins in human neuroblastoma cell model of rotenone neurotoxicity. Comparative study with myricetin and N-acetylcysteine. Toxicol Appl Pharmacol 2005;209:214-25.

Kostas V, Xilouri M, Emmanouilidou E, Rideout HJ, Stefanis L. Pathological roles of α-synuclein in neurological disorders. Lancet Neurol 2011;10:1015-25.

Khaled R, Moldzio R, Taha M, Rausch WD. Thymoquinone protects dopaminergic neurons against MPP+ and rotenone. Phytother Res 2009;23:696-700.

Takahiko F, Kanada N, Shimada A, Ogata M, Suzuki I, Hayashi I, et al. Effect of sesamin in Acanthopanax senticosus H ARMS on behavioral dysfunction in rotenone-induced parkinsonian rats. Biol Pharm Bull 2005;28:169-72.

Lu XH, Fleming SM, Meurers B, Ackerson LC, Mortazavi F, Lo V, et al. Bacterial artificial chromosome transgenic mice expressing a truncated mutant parkin exhibit age-dependent hypokinetic motor deficits, dopaminergic neuron degeneration, and accumulation of proteinase K-resistant α-synuclein. J Neurosci 2009;29:1962-76.

Wagner GC, Seiden LS, Schuster CR. Methamphetamine-induced changes in brain catecholamines in rats and guinea pigs. Drug Alcohol Depend 1979;4:435-8.



How to Cite

IMRAN, M., A. MISHRA, A. USMANI, and A. EQBAL. “EXPERIMENTAL ANIMAL MODELS OF PARKINSON’S DISEASE: AN OVERVIEW”. Asian Journal of Pharmaceutical and Clinical Research, vol. 13, no. 11, Nov. 2020, pp. 12-17, doi:10.22159/ajpcr.2020.v13i11.39131.



Review Article(s)