MPTP-Induced Mouse Model of Parkinson's Disease: Advantages, Limitations, and Breakthroughs
DOI:
https://doi.org/10.54097/54nzzw92Keywords:
Parkinson's Disease, MPTP, Animal Models, NeuroinflammationAbstract
Parkinson's disease (PD) is a common neurodegenerative disorder characterized pathologically by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta and the formation of Lewy bodies, which are neuronal inclusions primarily composed of abnormally aggregated α-synuclein. To elucidate the pathogenesis of PD and explore therapeutic strategies, researchers have established various animal models. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) reliably triggers neuroimmune cascades in the animal brain that closely mirror the pathological hallmarks of PD and selectively destroys dopaminergic neurons. MPTP-based mouse models have become one of the most widely used PD animal models. This review systematically summarizes the in vivo metabolism of MPTP, common protocols for establishing MPTP-induced mouse models, their pathological features, and further discusses the trends and limitations of this model.
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[1] WILSON D M 3RD, COOKSON M R, VAN DEN BOSCH L, et al. Hallmarks of neurodegenerative diseases[J]. Cell, 2023, 186(4): 693-714.
[2] RAO Y, DU S, YANG B, et al. NeuroD1 induces microglial apoptosis and cannot induce microglia-to-neuron cross-lineage reprogramming[J]. Neuron, 2021, 109(24): 4094-4108.e5.
[3] ZHANG J, FAN Y, LIANG H, et al. Global, regional and national temporal trends in Parkinson's disease incidence, disability-adjusted life year rates in middle-aged and older adults: a cross-national inequality analysis and Bayesian age-period-cohort analysis based on the global burden of disease 2021[J]. Neurological Sciences, 2025, 46(4): 1647-1660.
[4] ROCHA G S, FREIRE M A M, FALCAO D, et al. Neurodegeneration in Parkinson's disease: are we looking at the right spot? [J]. Molecular Brain, 2025, 18(1): 68.
[5] DAUER W, PRZEDBORSKI S. Parkinson's disease: mechanisms and models[J]. Neuron, 2003, 39(6): 889-909.
[6] CHAUDHARY S A, CHAUDHARY S, RAWAT S. Understanding Parkinson's disease: current trends and its multifaceted complications[J]. Frontiers in Aging Neuroscience, 2025, 17: 1617107.
[7] SRIVASTAVA R, DILNASHIN H, KAPOOR D, et al. Role of animal models in Parkinson's disease (PD): what role they play in preclinical translational research[J]. CNS & Neurological Disorders Drug Targets, 2024, 23(2): 181-202.
[8] BARKER R A, BJÖRKLUND A. Animal models of Parkinson's disease: are they useful or not? [J]. Journal of Parkinson's Disease, 2020, 10(4): 1335-1342.
[9] WEGRZYNOWICZ M, BAR-ON D, CALO' L, et al. Depopulation of dense α-synuclein aggregates is associated with rescue of dopamine neuron dysfunction and death in a new Parkinson's disease model[J]. Acta Neuropathologica, 2019, 138(4): 575-595.
[10] GUIMARÃES R P, RESENDE M C S, TAVARES M M, et al. Construct, face, and predictive validity of Parkinson's disease rodent models[J]. International Journal of Molecular Sciences, 2024, 25(16): 8971.
[11] SU C F, JIANG L, ZHANG X W, et al. Resveratrol in rodent models of Parkinson's disease: a systematic review of experimental studies[J]. Frontiers in Pharmacology, 2021, 12: 644219.
[12] FRANCARDO V, RECCHIA A, POPOVIC N, et al. Impact of the lesion procedure on the profiles of motor impairment and molecular responsiveness to L-DOPA in the 6-hydroxydopamine mouse model of Parkinson's disease[J]. Neurobiology of Disease, 2011, 42(3): 327-340.
[13] DODIYA H B, FORSYTH C B, VOIGT R M, et al. Chronic stress-induced gut dysfunction exacerbates Parkinson's disease phenotype and pathology in a rotenone-induced mouse model of Parkinson's disease[J]. Neurobiology of Disease, 2020, 135: 104352.
[14] BAE W Y, CHOI J S, JEONG J W. The Neuroprotective Effects of Cinnamic Aldehyde in an MPTP Mouse Model of Parkinson's Disease[J]. International Journal of Molecular Sciences, 2018, 19(2): 551.
[15] DOVONOU A, BOLDUC C, SOTO LINAN V, et al. Animal models of Parkinson's disease: bridging the gap between disease hallmarks and research questions[J]. Translational Neurodegeneration, 2023, 12(1): 36.
[16] BORSCHE M, PEREIRA S L, KLEIN C, et al. Mitochondria and Parkinson's Disease: Clinical, Molecular, and Translational Aspects[J]. Journal of Parkinson's Disease, 2021, 11(1): 45-60.
[17] LANGSTON J W, BALLARD P, TETRUD J W, et al. Chronic Parkinsonism in humans due to a product of meperidine-analog synthesis[J]. Science, 1983, 219(4587): 979-980.
[18] JAVITCH J A, D'AMATO R J, STRITTMATTER S M, et al. Parkinsonism-inducing neurotoxin, N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine: uptake of the metabolite N-methyl-4-phenylpyridine by dopamine neurons explains selective toxicity[J]. Proceedings of the National Academy of Sciences of the United States of America, 1985, 82(7): 2173-2177.
[19] WU D C, TEISMANN P, TIEU K, et al. NADPH oxidase mediates oxidative stress in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of Parkinson's disease[J]. Proceedings of the National Academy of Sciences of the United States of America, 2003, 100(10): 6145-6150.
[20] HU J, ZANG H, LI H, et al. Impaired autophagy from TRPV4 activation drives α-synuclein pathology in a Parkinson's disease model: a toxicological insight[J]. Toxicology and Applied Pharmacology, 2026, 511: 117825.
[21] SERRA M, FAUSTINI G, BREMBATI V, et al. Early α-synuclein/synapsin III co-accumulation, nigrostriatal dopaminergic synaptopathy and denervation in the MPTPp mouse model of Parkinson's disease[J]. Experimental Neurology, 2025, 383: 115040.
[22] CHEN Z, LIU Y, ZHAO J, et al. PHLPP1 deficiency alleviates dopaminergic neurodegeneration and represses neuroinflammation in Parkinson's disease[J]. Behavioral and Brain Functions, 2025, 21(1): 29.
[23] SEO J, LEE Y, KIM B S, et al. A non-human primate model for stable chronic Parkinson's disease induced by MPTP administration based on individual behavioral quantification[J]. Journal of Neuroscience Methods, 2019, 311: 277-287.
[24] BLESA J, PRZEDBORSKI S. Parkinson's disease: animal models and dopaminergic cell vulnerability[J]. Frontiers in Neuroanatomy, 2014, 8: 155.
[25] GUO Q, WANG Y, YU L, et al. Nicotine restores olfactory function by activation of prok2R/Akt/FoxO3a axis in Parkinson's disease[J]. Journal of Translational Medicine, 2024, 22(1): 350.
[26] ÖZKAN A, BÜLBÜL M, DERIN N, et al. Neuropeptide-S affects cognitive impairment and depression-like behavior on MPTP induced experimental mouse model of Parkinson's disease[J]. Turkish Journal of Medical Sciences, 2021, 51(6): 3126-3135.
[27] OLIVEIRA B D S, TOSCANO E C B, ABREU L K S, et al. Nigrostriatal inflammation is associated with nonmotor symptoms in an experimental model of prodromal Parkinson's disease[J]. Neuroscience, 2024, 549: 65-75.
[28] YANG R, YE S, ZHANG S, et al. Serotonin and dopamine depletion in distinct brain regions may cause anxiety in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated mice as a model of early Parkinson's disease[J]. NeuroReport, 2023, 34(11): 551-559.
[29] LIU L, HSU S S, KALIA S K, et al. Injury and strain-dependent dopaminergic neuronal degeneration in the substantia nigra of mice after axotomy or MPTP[J]. Brain Research, 2003, 994(2): 243-252.
[30] REN J, LIU T, YOU L, et al. Time association study on a sub-acute mouse model of Parkinson's disease[J]. Heliyon, 2024, 10(13): e34082.
[31] DROLET R E, BEHROUZ B, LOOKINGLAND K J, et al. Mice lacking alpha-synuclein have an attenuated loss of striatal dopamine following prolonged chronic MPTP administration[J]. Neurotoxicology, 2004, 25(5): 761-769.
[32] MERGHANI M M, ARDAH M T, AL SHAMSI M, et al. Dose-related biphasic effect of the Parkinson's disease neurotoxin MPTP on the spread, accumulation, and toxicity of α-synuclein[J]. Neurotoxicology, 2021, 84: 41-52.
[33] POTASHKIN J A, BLUME S R, RUNKLE N K. Limitations of animal models of Parkinson's disease[J]. Parkinson's Disease, 2011, 2011: 658083.
[34] HEINEMANN S D, POSIMO J M, MASON D M, et al. Synergistic stress exacerbation in hippocampal neurons: evidence favoring the dual-hit hypothesis of neurodegeneration[J]. Hippocampus, 2016, 26(8): 980-994.
[35] LEE S, OH S T, JEONG H J, et al. MPTP-induced vulnerability of dopamine neurons in A53T α-synuclein overexpressed mice with the potential involvement of DJ-1 downregulation[J]. Korean Journal of Physiology and Pharmacology, 2017, 21(6): 625-632.
[36] JEONG H J, KIM D W, WOO S J, et al. Transduced Tat-DJ-1 protein protects against oxidative stress-induced SH-SY5Y cell death and Parkinson disease in a mouse model[J]. Molecules and Cells, 2012, 33(5): 471-478.
[37] SUN Y, WANG Y, ZHAO X, et al. Nuclear translocation of DJ-1 protects adult neuronal stem cells in an MPTP mouse model of Parkinson's disease[J]. NeuroReport, 2018, 29(4): 301-307.
[38] MARTIN L J, SEMENKOW S, HANAFORD A, et al. Mitochondrial permeability transition pore regulates Parkinson's disease development in mutant α-synuclein transgenic mice[J]. Neurobiology of Aging, 2014, 35(5): 1132-1152.
[39] LI H Y, LI M Z, CHEN M X, et al. The comparison of ferroptosis characteristics and motor deficits in Parkinson's disease mouse models[J]. The Journal of Practical Medicine, 2025, 41(22): 3501-3509.
[40] SHU H, HUANG X, SU Z, et al. RRx-001 ameliorates astrocyte pyroptosis by regulating LCN2-NLRP3 inflammasome activation in an MPTP-induced parkinson's disease mouse model[J]. Cellular and Molecular Life Sciences, 2026, 83(1): 60.
[41] CHENG Y, JIANG C, ZHANG Z, et al. Tracking ClO⁻ dynamics during the progression of Parkinson's disease in MPTP mouse model using in vivo brain microdialysis[J]. ACS Chemical Neuroscience, 2026, 17(9): 1658-1669.
[42] SHMUELY H, RIVLIN M, PERLMAN O. Quantitative multi-metabolite imaging of Parkinson's disease using AI boosted molecular MRI[J]. npj Imaging, 2025, 3(1): 66.
[43] TANG X, XUE J, CHEN R, et al. Behavioral, biochemical, and molecular characterization of MPTP/p-intoxicated mice[J]. Experimental Neurology, 2025, 386: 115168.
[44] WEI J, WANG L, WANG D, et al. Capsaicin and nicotine alleviate MPTP induced olfactory dysfunction by suppressing cGAS/TBK1/STING and MAPK mediated neuroinflammation [J]. npj Parkinson's Disease, 2025, 11(1): 285.
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