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Neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) as a Parkinson’s Disease Model

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Handbook of Neurotoxicity

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Abstract

Administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to susceptible animals is the most popular means for modeling the destruction of the nigrostriatal dopaminergic neurons seen in Parkinson’s disease (PD). MPTP causes a damage to the substantia nigra pars compacta (SNpc) dopaminergic neurons and depletes striatal dopamine secretion in nonhuman primates and rodents. MPTP passes through the blood–brain barrier (BBB) and is converted, mainly in glial cells, into its active form, 1-methyl-4-phenylpyridinium (MPP+), by an enzyme, monoamine oxidase B (MAO-B). MPP+ is selectively transported into dopaminergic nerve terminals through dopamine transporter (DAT) and finally induces dopaminergic cell loss. The selective neurotoxicity of MPTP to neural tissues other than the dopaminergic system, such as the subventricular zone (SVZ) and rostral migratory stream (RMS) in the adult brain, has been indicated. The cells undergoing apoptosis in the SVZ are A cells and MAO-B inhibitors completely protected against the neurotoxicity, suggesting that the MPTP neurotoxicity to A cells is mediated by the conversion of MPTP into MPP+ by MAO-B. The neurotoxicity of MPTP to neuroblasts in the SVZ does not require DAT or other monoamine transporters. There is a strain difference in the susceptibility of the MPTP neurotoxicity between susceptible C57BL/6 and resistant BALB/c mice. However, MAO-B, DAT, neural NOS (nNOS), and inducible NOS (iNOS) expression levels do not influence the strain susceptibility to MPTP. MPTP and MPP+ can pass through the placenta and embryonic or newborn BBB, and finally reach the brain. The number of MAO-B-positive glial cells in the brain increases in MPTP-treated embryonic and newborn mice, indicating the involvement of MAO-B in the acute neurotoxicity. MPTP or MPP+ administration into embryonic and newborn mice causes a loss of TH-positive cells and fibers in the nigrostriatal system and increases the number of apoptotic cells in the SVZ. Delayed regeneration of dopaminergic neurons due to the loss of SVZ A cells may be one of possible causes of the pathological condition. With increased attention to dopaminergic neurogenesis in MPTP-induced animal models, such animals become useful as a tool for establishing the contact to PD on neurogenesis.

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Abbreviations

6-OHDA:

6-Hydroxydopamine

BBB:

Blood–brain barrier

BrdU:

Bromodeoxyuridine

CNS:

Central nervous system

DA:

Dopamine

DAT:

Dopamine transporter

DCX:

Doublecortin

DG:

Dentate gyrus

icv:

Intracerebroventricularly

iNOS:

Inducible NOS

MAO-B:

Monoamine oxidase B

MMPs:

Metalloproteinases

MPDP+ :

1-Methyl-4-phenyl-2,3-dihydropyridinium

MPP+ :

1-Methyl-4-phenylpyridinium

MPTP:

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine

nNOS:

Neural NOS

NOS:

Nitric oxide synthase

OB:

Olfactory bulb

PCNA:

Proliferating cell nuclear antigen

PD:

Parkinson’s disease

RMS:

Rostral migratory stream

Ro 16-6491:

N-(2-aminoethyl)-4-chlorobenzamide

SERT:

Serotonin transporter

SGZ:

Subgranular zone

SN:

Substantia nigra

SNpc:

Substantia nigra pars compacta

SVZ:

Subventricular zone

TH:

Tyrosine hydroxylase

TUNEL:

Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling

VMAT2:

Vesicular monoamine transporter 2

References

  • Altman, J. (1963). Autoradiographic investigation of cell proliferation in the brains of rats and cats. Anatomical Record, 145, 573–591.

    Article  CAS  PubMed  Google Scholar 

  • Altman, J., & Das, G. D. (1965). Autoradiographic and histological evidence of postnatal hippocampal neurogenesis in rats. The Journal of Comparative Neurology, 124, 319–335.

    Article  CAS  PubMed  Google Scholar 

  • Andrews, A. M., & Murphy, D. L. (1993). Fluoxetine and desipramine selectively attenuate 2′-NH2-MPTP-induced depletions in serotonin and norepinephrine. European Journal of Pharmacology, 250, 215–221.

    Article  CAS  PubMed  Google Scholar 

  • Bernier, P. J., Vinet, J., Cossette, M., & Parent, A. (2000). Characterization of the subventricular zone of the adult human brain: Evidence for the involvement of Bcl-2. Neurosciences Research, 37, 67–78.

    Article  CAS  Google Scholar 

  • Bezard, E., Gross, C. E., Fournier, M. C., Dovero, S., Bloch, B., & Jaber, M. (1999). Absence of MPTP-induced neuronal death in mice lacking the dopamine transporter. Experimental Neurology, 155, 268–273.

    Article  CAS  PubMed  Google Scholar 

  • Biebl, M., Cooper, C. M., Winkler, J., & Kuhn, H. G. (2000). Analysis of neurogenesis and programmed cell death reveals a self-renewing capacity in the adult rat brain. Neuroscience Letters, 291, 17–20.

    Article  CAS  PubMed  Google Scholar 

  • Blum, D., Torch, S., Lambeng, N., et al. (2001). Molecular pathways involved in the neurotoxicity of 6-OHDA, dopamine and MPTP: Contribution to the apoptotic theory in Parkinson’s disease. Progress in Neurobiology, 65, 135–172.

    Article  CAS  PubMed  Google Scholar 

  • Blume, E. (1983). Street drugs yield primate Parkinson’s model. The Journal of the American Medical Association, 250, 13–14.

    Article  CAS  Google Scholar 

  • Borta, A., & Hoglinger, G. U. (2007). Dopamine and adult neurogenesis. Journal of Neurochemistry, 100, 587–595.

    Article  CAS  PubMed  Google Scholar 

  • Bovetti, S., Bovolin, P., Perroteau, I., & Puche, A. C. (2007). Subventricular zone-derived neuroblast migration to the olfactory bulb is modulated by matrix remodelling. European Journal of Neuroscience, 25, 2021–2033.

    Article  PubMed  Google Scholar 

  • Brunjes, P. C., & Armstrong, A. M. (1996). Apoptosis in the rostral migratory stream of the developing rat. Brain Research. Developmental Brain Research, 92, 219–222.

    Article  CAS  PubMed  Google Scholar 

  • Burns, R. S., Chiueh, C. C., Markey, S. P., Ebert, M. H., Jacobowitz, D. M., & Kopin, I. J. (1983). A primate model of Parkinsonism: Selective destruction of dopaminergic neurons in the pars compacta of the substantia nigra by N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Proceedings of the National Academy of Sciences of the United States of America, 80, 4546–4550.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Cameron, H. A., Woolley, C. S., McEwen, B. S., & Gould, E. (1993). Differentiation of newly born neurons and glia in the dentate gyrus of the adult rat. Neuroscience, 56, 337–344.

    Article  CAS  PubMed  Google Scholar 

  • Chalimoniuk, M., Lukacova, N., Marsala, J., & Langfort, J. (2006). Alterations of the expression and activity of midbrain nitric oxide synthase and soluble guanylyl cyclase in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Parkinsonism in mice. Neuroscience, 141, 1033–1046.

    Article  CAS  PubMed  Google Scholar 

  • Chiba, K., Trevor, A. J., & Castagnoli, N., Jr. (1985). Active uptake of MPP+, a metabolite of MPTP, by brain synaptosomes. Biochemical and Biophysical Research Communications, 128, 1228–1232.

    Article  CAS  PubMed  Google Scholar 

  • Chiueh, C. C., Markey, S. P., Burns, R. S., Johannessen, J. N., Pert, A., & Kopin, I. J. (1984). Neurochemical and behavioral effects of systemic and intranigral administration of N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in the rat. European Journal of Pharmacology, 100, 189–194.

    Article  CAS  PubMed  Google Scholar 

  • Desole, M. S., Sciola, L., Delogu, M. R., Sircana, S., Migheli, R., & Miele, E. (1997). Role of oxidative stress in the manganese and 1-methyl-4-(2-ethylphenyl)- 1,2,3,6-tetrahydropyridine-induced apoptosis in PC12 cells. Neurochemistry International, 31, 169–176.

    Article  CAS  PubMed  Google Scholar 

  • Dipasquale, B., Mariani, A. M., & Youle, R. J. (1991). Apoptosis and DNA degradation induced by 1-methyl-4-phenylpyridinium in neurons. Biochemical and Biophysical Research Communications, 181, 1442–1448.

    Article  CAS  PubMed  Google Scholar 

  • Doetsch, F., & Alvarez-Buylla, A. (1996). Network of tangential pathways for neuronal migration in adult mammalian brain. Proceedings of the National Academy of Sciences of the United States of America, 93, 14895–14900.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Doetsch, F., Garcia-Verdugo, J. M., & Alvarez-Buylla, A. (1997). Cellular composition and three-dimensional organization of the subventricular germinal zone in the adult mammalian brain. Journal of Neuroscience, 17, 5046–5061.

    CAS  PubMed  Google Scholar 

  • Doetsch, F., Caille, I., Lim, D. A., Garcia-Verdugo, J. M., & Alvarez-Buylla, A. (1999). Subventricular zone astrocytes are neural stem cells in the adult mammalian brain. Cell, 97, 703–716.

    Article  CAS  PubMed  Google Scholar 

  • Doetsch, F., Petreanu, L., Caille, I., Garcia-Verdugo, J. M., & Alvarez-Buylla, A. (2002). EGF converts transit-amplifying neurogenic precursors in the adult brain into multipotent stem cells. Neuron, 36, 1021–1034.

    Article  CAS  PubMed  Google Scholar 

  • Du, Y., Dodel, R. C., Bales, K. R., Jemmerson, R., Hamilton-Byrd, E., & Paul, S. M. (1997). Involvement of a caspase-3-like cysteine protease in 1-methyl-4-phenylpyridinium-mediated apoptosis of cultured cerebellar granule neurons. Journal of Neurochemistry, 69, 1382–1388.

    Article  CAS  PubMed  Google Scholar 

  • Eriksson, P. S., Perfilieva, E., Bjork-Eriksson, T., Alborn, A. M., Nordborg, C., Peterson, D. A., & Gage, F. H. (1998). Neurogenesis in the adult human hippocampus. Nature Medicine, 4, 1313–1317.

    Article  CAS  PubMed  Google Scholar 

  • Filipov, N. M., Norwood, A. B., & Sistrunk, S. C. (2009). Strain-specific sensitivity to MPTP of C57BL/6 and BALB/c mice is age dependent. Neuroreport, 20, 713–717.

    Article  CAS  PubMed  Google Scholar 

  • Freundlieb, N., Francois, C., Tande, D., Oertel, W. H., Hirsch, E. C., & Hoglinger, G. U. (2006). Dopaminergic substantia nigra neurons project topographically organized to the subventricular zone and stimulate precursor cell proliferation in aged primates. Journal of Neuroscience, 26, 2321–2325.

    Article  CAS  PubMed  Google Scholar 

  • Gainetdinov, R. R., Fumagalli, F., Jones, S. R., & Caron, M. G. (1997). Dopamine transporter is required for in vivo MPTP neurotoxicity: Evidence from mice lacking the transporter. Journal of Neurochemistry, 69, 1322–1325.

    Article  CAS  PubMed  Google Scholar 

  • Garcia-Verdugo, J. M., Doetsch, F., Wichterle, H., Lim, D. A., & Alvarez-Buylla, A. (1998). Architecture and cell types of the adult subventricular zone: In search of the stem cells. Journal of Neurobiology, 36, 234–248.

    Article  CAS  PubMed  Google Scholar 

  • Gerlach, M., & Riederer, P. (1996). Animal models of Parkinson’s disease: An empirical comparison with the phenomenology of the disease in man. Journal of Neural Transmission, 103, 987–1041.

    Article  CAS  PubMed  Google Scholar 

  • German, D. C., Liang, C. L., Manaye, K. F., Lane, K., & Sonsalla, P. K. (2000). Pharmacological inactivation of the vesicular monoamine transporter can enhance 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurodegeneration of midbrain dopaminergic neurons, but not locus coeruleus noradrenergic neurons. Neuroscience, 101, 1063–1069.

    Article  CAS  PubMed  Google Scholar 

  • Gould, E., Tanapat, P., McEwen, B. S., Flugge, G., & Fuchs, E. (1998). Proliferation of granule cell precursors in the dentate gyrus of adult monkeys is diminished by stress. Proceedings of the National Academy of Sciences of the United States of America, 95, 3168–3171.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Gould, E., Reeves, A. J., Fallah, M., Tanapat, P., Gross, C. G., & Fuchs, E. (1999a). Hippocampal neurogenesis in adult old world primates. Proceedings of the National Academy of Sciences of the United States of America, 96, 5263–5267.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Gould, E., Reeves, A. J., Graziano, M. S., & Gross, C. G. (1999b). Neurogenesis in the neocortex of adult primates. Science, 286, 548–552.

    Article  CAS  PubMed  Google Scholar 

  • Hamre, K., Tharp, R., Poon, K., Xiong, X., & Smeyne, R. J. (1999). Differential strain susceptibility following 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration acts in an autosomal dominant fashion: Quantitative analysis in seven strains of Mus musculus. Brain Research, 828, 91–103.

    Article  CAS  PubMed  Google Scholar 

  • Hartley, A., Stone, J. M., Heron, C., Cooper, J., & Schapira, A. H. V. (1994). Complex I inhibitors induce dose-dependent apoptosis in PC12 cells: Relevance to Parkinson’s disease. Journal of Neurochemistry, 63, 1987–1990.

    Article  CAS  PubMed  Google Scholar 

  • He, X. J., & Nakayama, H. (2009). Neurogenesis in neurotoxin-induced animal models for Parkinson’s disease – a review of the current status. Journal of Toxicologic Pathology, 22, 101–108.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • He, X. J., Nakayama, H., Ueno, M., & Doi, K. (2004). Age-dependent susceptibility to MPTP neurotoxicity in C57BL mice: A tyrosine hydroxylase-immunohistochemical evaluation. Journal of Toxicologic Pathology, 17, 239–244.

    Article  CAS  Google Scholar 

  • He, X. J., Nakayama, H., Dong, M., Yamauchi, H., Ueno, M., Uetsuka, K., & Doi, K. (2006). Evidence of apoptosis in the subventricular zone and rostral migratory stream in the MPTP mouse model of Parkinson disease. Journal of Neuropathology and Experimental Neurology, 65, 873–882.

    Article  CAS  PubMed  Google Scholar 

  • He, X. J., Yamauchi, H., Uetsuka, K., & Nakayama, H. (2008a). Neurotoxicity of MPTP to migrating neuroblasts: Studies in acute and subacute mouse models of Parkinson’s disease. Neurotoxicology, 29, 413–420.

    Article  CAS  PubMed  Google Scholar 

  • He, X. J., Uetsuka, K., & Nakayama, H. (2008b). Neural progenitor cells are protected against MPTP by MAO-B inhibitors. Neurotoxicology, 29, 1141–1146.

    Article  CAS  PubMed  Google Scholar 

  • Heikkila, R. E., Cabbat, F. S., Manzino, L., & Duvoisin, R. C. (1984). Effects of 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine on neostriatal dopamine in mice. Neuropharmacology, 23, 711–713.

    Article  CAS  PubMed  Google Scholar 

  • Hoglinger, G. U., Rizk, P., Muriel, M. P., Duyckaerts, C., Oertel, W. H., Caille, I., & Hirsch, E. C. (2004). Dopamine depletion impairs precursor cell proliferation in Parkinson disease. Nature Neuroscience, 7, 726–735.

    Article  PubMed  Google Scholar 

  • Itano, Y., & Nomura, Y. (1995). 1-methyl-4-phenylpyridinium ion (MPP+) causes DNA fragmentation and increases the Bcl-2 expression in human neuroblastoma, SH-SY5Y cells through different mechanism. Brain Research, 704, 240–245.

    Article  CAS  PubMed  Google Scholar 

  • Ito, T., Suzuki, K., Uchida, K., & Nakayama, H. (2013a). Different susceptibility to 1-methyl-4-phenylpyridium (MPP+)-induced nigro-striatal dopaminergic cell loss between C57BL/6 and BALB/c mice is not related to the difference of monoamine oxidase-B (MAO-B). Experimental and Toxicologic Pathology, 65, 153–158.

    Article  CAS  PubMed  Google Scholar 

  • Ito, T., Uchida, K., & Nakayama, H. (2013b). Neuronal or inducible nitric oxide synthase (NOS) expression level is not involved in the different susceptibility to nigro-striatal dopaminergic neurotoxicity induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) between C57BL/6 and BALB/c mice. Experimental and Toxicologic Pathology, 65, 121–125.

    Article  CAS  PubMed  Google Scholar 

  • Javitch, J. A., D′Amato, R. J., Strittmatter, S. M., & Snyder, S. H. (1985). 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. Proceedings of the National Academy of Sciences of the United States of America, 82, 2173–2177.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Joniec, I., Ciesielska, A., Kurkowska-Jastrzebska, I., Przybylkowski, A., Czlonkowska, A., & Czlonkowski, A. (2009). Age- and sex-differences in the nitric oxide synthase expression and dopamine concentration in the murine model of Parkinson’s disease induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Brain Research, 1261, 7–19.

    Article  CAS  PubMed  Google Scholar 

  • Kaplan, M. S., & Hinds, J. W. (1977). Neurogenesis in the adult rat: Electron microscopic analysis of light radioautographs. Science, 197, 1092–1094.

    Article  CAS  PubMed  Google Scholar 

  • Kempermann, G., Jessberger, S., Steiner, B., & Kronenberg, G. (2004). Milestones of neuronal development in the adult hippocampus. Trends in Neurosciences, 27, 447–452.

    Article  CAS  PubMed  Google Scholar 

  • Kuhn, H. G., Dickinson-Anson, H., & Gage, F. H. (1996). Neurogenesis in the dentate gyrus of the adult rat: Age-related decrease of neuronal progenitor proliferation. Journal of Neuroscience, 16, 2027–2033.

    CAS  PubMed  Google Scholar 

  • Langston, J. W., Ballard, P., Tetrud, J. W., & Irwin, I. (1983). Chronic Parkinsonism in humans due to a product of meperidine-analog synthesis. Science, 219, 979–980.

    Article  CAS  PubMed  Google Scholar 

  • Langston, J. W., Forno, L. S., Rebert, C. S., & Irwin, I. (1984). Selective nigral toxicity after systemic administration of 1-methyl-4-phenyl-1,2,5,6-tetrahydropyrine (MPTP) in the squirrel monkey. Brain Research, 292, 390–394.

    Article  CAS  PubMed  Google Scholar 

  • Levison, S. W., Rothstein, R. P., Brazel, C. Y., Young, G. M., & Albrecht, P. J. (2000). Selective apoptosis within the rat subependymal zone: A plausible mechanism for determining which lineages develop from neural stem cells. Developmental Neuroscience, 22, 106–115.

    Article  CAS  PubMed  Google Scholar 

  • Liu, Y., & Edwards, R. H. (1997). The role of vesicular transport proteins in synaptic transmission and neural degeneration. Annual Review of Neuroscience, 20, 125–156.

    Article  CAS  PubMed  Google Scholar 

  • Lois, C., & Alvarez-Buylla, A. (1994). Long-distance neuronal migration in the adult mammalian brain. Science, 264, 1145–1148.

    Article  CAS  PubMed  Google Scholar 

  • Melamed, E., Rosenthal, J., & Youdim, M. B. (1990). Immunity of fetal mice to prenatal administration of the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine. Journal of Neurochemistry, 55, 1427–1431.

    Article  CAS  PubMed  Google Scholar 

  • Mitra, N., Mohanakumar, K. P., & Ganguly, D. K. (1994). Resistance of golden hamster to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine: Relationship with low levels of regional monoamine oxidase B. Journal of Neurochemistry, 62, 1906–1912.

    Article  CAS  PubMed  Google Scholar 

  • Mochizuki, H., Nakamura, N., Nishi, K., & Mizuno, Y. (1994). Apoptosis is induced by 1-methyl-4-phenylpyridinium ion (MPP+) in ventral mesencephalic-striatal co-culture in rat. Neuroscience Letters, 170, 191–194.

    Article  CAS  PubMed  Google Scholar 

  • Muthian, G., Mackey, V., King, J., & Charlton, C. G. (2010). Modeling a sensitization stage and a precipitation stage for Parkinson’s disease using prenatal and postnatal 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine administration. Neuroscience, 169, 1085–1093.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Ng, K. L., Li, J. D., Cheng, M. Y., Leslie, F. M., Lee, A. G., & Zhou, Q. Y. (2005). Dependence of olfactory bulb neurogenesis on prokineticin 2 signaling. Science, 308, 1923–1927.

    Article  CAS  PubMed  Google Scholar 

  • Ohtani, N., Goto, T., Waeber, C., & Bhide, P. G. (2003). Dopamine modulates cell cycle in the lateral ganglionic eminence. Journal of Neuroscience, 23, 2840–2850.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Parkinson, J. (1817). An essay on the shaking palsy. The Journal of Neuropsychiatry and Clinical Neurosciences, 14, 223–236.

    Article  Google Scholar 

  • Pencea, V., Bingaman, K. D., Freedman, L. J., & Luskin, M. B. (2001). Neurogenesis in the subventricular zone and rostral migratory stream of the neonatal and adult primate forebrain. Experimental Neurology, 172, 1–16.

    Article  CAS  PubMed  Google Scholar 

  • Peng, J., Xie, L., Jin, K., Greenberg, D. A., & Andersen, J. K. (2008). Fibroblast growth factor 2 enhances striatal and nigral neurogenesis in the acute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of Parkinson’s disease. Neuroscience, 153, 664–670.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Perese, D. A., Ulman, J., Viola, J., Ewing, S. E., & Bankiewicz, K. S. (1989). A 6-hydroxydopamine-induced selective Parkinsonian rat model. Brain Research, 494, 285–293.

    Article  CAS  PubMed  Google Scholar 

  • Pifl, C., Giros, B., & Caron, M. G. (1993). Dopamine transporter expression confers cytotoxicity to low doses of the Parkinsonism-inducing neurotoxin 1-methyl-4-phenylpyridinium. Journal of Neuroscience, 13, 4246–4253.

    CAS  PubMed  Google Scholar 

  • Popolo, M., McCarthy, D. M., & Bhide, P. G. (2004). Influence of dopamine on precursor cell proliferation and differentiation in the embryonic mouse telencephalon. Developmental Neuroscience, 26, 229–244.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Privat, A., & Leblond, C. P. (1972). The subependymal layer and neighboring region in the brain of the young rat. The Journal of Comparative Neurology, 146, 277–302.

    Article  CAS  PubMed  Google Scholar 

  • Przedborski, S., & Ischiropoulos, H. (2005). Reactive oxygen and nitrogen species: Weapons of neuronal destruction in models of Parkinson’s disease. Antioxidants & Redox Signaling, 7, 685–693.

    Article  CAS  Google Scholar 

  • Przedborski, S., & Vila, M. (2001). MPTP: A review of its mechanism of neurotoxicity. Clinical Neuroscience Research, 1, 407–418.

    Article  CAS  Google Scholar 

  • Przedborski, S., & Vila, M. (2003). The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model: A tool to explore the pathogenesis of Parkinson’s disease. Annals of the New York Academy of Sciences, 991, 189–198.

    Article  CAS  PubMed  Google Scholar 

  • Przedborski, S., Jackson-Lewis, V., Naini, A. B., Jakowec, M., Petzinger, G., Miller, R., & Akram, M. (2001). The Parkinsonian toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP): A technical review of its utility and safety. Journal of Neurochemistry, 76, 1265–1274.

    Article  CAS  PubMed  Google Scholar 

  • Przedbroski, S., Leviver, M., Jiang, H., Ferreira, M., Jackson-Lewis, V., Donaldson, D., & Togasaki, D. M. (1995). Dose-dependent lesions of the dopaminergic nigrostriatal pathway induced by instrastriatal injection of 6-hydroxydopamine. Neuroscience, 67, 631–647.

    Article  Google Scholar 

  • Quinones-Hinojosa, A., Sanai, N., Soriano-Navarro, M., Gonzalez-Perez, O., Mirzadeh, Z., Gil-Perotin, S., Romero-Rodriguez, R., Berger, M. S., Garcia-Verdugo, J. M., & Alvarez-Buylla, A. (2006). Cellular composition and cytoarchitecture of the adult human subventricular zone: A niche of neural stem cells. The Journal of Comparative Neurology, 494, 415–434.

    Article  PubMed  Google Scholar 

  • Reinhard, J. F., Jr., Daniels, A. J., & Viveros, O. H. (1988). Potentiation by reserpine and tetrabenazine of brain catecholamine depletion by MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) in the mouse; evidence for subcellular sequestration as basis for cellular resistance to the toxicant. Neuroscience Letters, 90, 349–353.

    Article  CAS  PubMed  Google Scholar 

  • Riachi, N. J., & Harik, S. I. (1988). Strain differences in systemic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine neurotoxicity in mice correlate best with monoamine oxidase activity at the blood–brain barrier. Life Sciences, 42, 2359–2363.

    Article  CAS  PubMed  Google Scholar 

  • Rommelfanger, K. S., Weinshenker, D., & Miller, G. W. (2004). Reduced MPTP toxicity in noradrenaline transporter knockout mice. Journal of Neurochemistry, 91, 1116–1124.

    Article  CAS  PubMed  Google Scholar 

  • Sai, T., Uchida, K., & Nakayama, H. (2013). Acute toxicity of MPTP and MPP+ in the brain of embryo and newborn mice. Experimental and Toxicologic Pathology, 65, 113–119.

    Article  CAS  PubMed  Google Scholar 

  • Sedelis, M., Hofele, K., Auburger, G. W., Morgan, S., Huston, J. P., & Schwarting, R. K. (2000). MPTP susceptibility in the mouse: Behavioral, neurochemical, and histological analysis of gender and strain differences. Behavior Genetics, 30, 171–182.

    Article  CAS  PubMed  Google Scholar 

  • Seri, B., Garcia-Verdugo, J. M., McEwen, B. S., & Alvarez-Buylla, A. (2001). Astrocytes give rise to new neurons in the adult mammalian hippocampus. Journal of Neuroscience, 21, 7153–7160.

    CAS  PubMed  Google Scholar 

  • Serra, P. A., Sciola, L., Delogu, M. R., Spano, A., Monaco, G., Miele, E., Rocchitta, G., Miele, M., Migheli, R., & Desole, M. S. (2002). The neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine induces apoptosis in mouse nigrostriatal glia. Relevance to nigral neuronal death and striatal neurochemical changes. Journal of Biological Chemistry, 277, 34451–34461.

    Article  CAS  PubMed  Google Scholar 

  • Shan, X., Chi, L., Bishop, M., Luo, C., Lien, L., Zhang, Z., & Liu, R. (2006). Enhanced de novo neurogenesis and dopaminergic neurogenesis in the substantia nigra of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Parkinson’s disease-like mice. Stem Cells, 24, 1280–1287.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Sheehan, J. P., Palmer, P. E., Helm, G. A., & Tuttle, J. B. (1997). MPP+ induced apoptotic cell death in SH-SY5Y neuroblastoma cells: An electron microscope study. Journal of Neuroscience Research, 48, 226–237.

    Article  CAS  PubMed  Google Scholar 

  • Shibui, Y., He, X. J., Uchida, K., & Nakayama, H. (2009). MPTP-induced neuroblast apoptosis in the subventricular zone is not regulated by dopamine or other monoamine transporters. Neurotoxicology, 30, 1036–1044.

    Article  CAS  PubMed  Google Scholar 

  • Simola, N., Morelli, M., & Carta, A. R. (2007). The 6-hydroxydopamine model of Parkinson’s disease. Neurotoxicity Research, 11, 151–167.

    Article  CAS  PubMed  Google Scholar 

  • Spencer, G. E., Klumperman, J., & Syed, N. I. (1998). Neurotransmitters and neurodevelopment. Role of dopamine in neurite outgrowth, target selection and specific synapse formation. Perspectives on Developmental Neurobiology, 5, 451–467.

    CAS  PubMed  Google Scholar 

  • Spooren, W. P., Gentsch, C., & Wiessner, C. (1998). TUNEL-positive cells in the substantia nigra of C57BL/6 mice after a single bolus of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Neuroscience, 85, 649–651.

    Article  CAS  PubMed  Google Scholar 

  • Staal, R. G., & Sonsalla, P. K. (2000). Inhibition of brain vesicular monoamine transporter (VMAT2) enhances 1-methyl-4-phenylpyridinium neurotoxicity in vivo in rat striata. Journal of Pharmacology and Experimental Therapeutics, 293, 336–342.

    CAS  PubMed  Google Scholar 

  • Sundstrom, E., Stromberg, I., Tsutsumi, T., Olson, L., & Jonsson, G. (1987). Studies on the effect of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on central catecholamine neurons in C57BL/6 mice. Comparison with three other strains of mice. Brain Research, 405, 26–38.

    Article  CAS  PubMed  Google Scholar 

  • Takahashi, N., Miner, L. L., Sora, I., Ujike, H., Revay, R. S., Kostic, V., Jackson-Lewis, V., Przedborski, S., & Uhl, G. R. (1997). VMAT2 knockout mice: Heterozygotes display reduced amphetamine-conditioned reward, enhanced amphetamine locomotion, and enhanced MPTP toxicity. Proceedings of the National Academy of Sciences of the United States of America, 94, 9938–9943.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Tatton, N. A., & Kish, S. J. (1997). In situ detection of apoptotic nuclei in the substantia nigra compacta of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated mice using terminal deoxynucleotidyl transferase labelling and acridine orange staining. Neuroscience, 77, 1037–1048.

    Article  CAS  PubMed  Google Scholar 

  • Vila, M., & Przedborski, S. (2003). Targeting programmed cell death neurodegenerative diseases. Nature Reviews Neuroscience, 4, 365–375.

    Article  CAS  PubMed  Google Scholar 

  • Vila, M., Jackson-Lewis, V., Vukosavic, S., et al. (2001). Bax ablation prevents dopaminergic neurodegeneration in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson’s disease. Proceedings of the National Academy of Sciences of the United States of America, 98, 2837–2842.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Wolfgang, S., & Beat, U. (1991). Placental toxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in mice. Toxicology, 67, 63–74.

    Article  Google Scholar 

  • Yasuda, Y., Shimoda, T., Uno, K., Tateishi, N., Furuya, S., Yagi, K., Suzuki, K., & Fujita, S. (2008). The effects of MPTP on the activation of microglia/astrocytes and cytokine/chemokine levels in different mice strains. Journal of Neuroimmunology, 204, 43–51.

    Article  CAS  PubMed  Google Scholar 

  • Zhao, M., Momma, S., Delfani, K., Carlen, M., Cassidy, R. M., Johansson, C. B., Brismar, H., Shupliakov, O., Frisen, J., & Janson, A. M. (2003). Evidence for neurogenesis in the adult mammalian substantia nigra. Proceedings of the National Academy of Sciences of the United States of America, 100, 7925–7930.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Zhao, C., Deng, W., & Gage, F. H. (2008). Mechanisms and functional implications of adult neurogenesis. Cell, 132, 645–660.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Veterinary Pathology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan

    H. Nakayama, T. Ito, Y. Shibui, T. Sai, K. Uchida & X. J. He

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  1. H. Nakayama
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  2. T. Ito
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  3. Y. Shibui
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  4. T. Sai
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  5. K. Uchida
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  6. X. J. He
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Correspondence to H. Nakayama .

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  1. Department of Biomedical Sciences, East Tennessee State University, Johnson City, Tennessee, USA

    Richard M. Kostrzewa

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Nakayama, H., Ito, T., Shibui, Y., Sai, T., Uchida, K., He, X.J. (2014). Neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) as a Parkinson’s Disease Model. In: Kostrzewa, R. (eds) Handbook of Neurotoxicity. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-5836-4_9

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