Iron-mediated bioactivation of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in glial cultures
Abstract
Primary cultures of mouse astrocytes were treated with both the monoamine oxidase (MAO) A inhibitor, clorgyline, and the MAO B inhibitor, deprenyl, prior to the addition of the neurotoxicant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Production of the 1-methyl-4-phenylpyridinium (MPP+) toxic metabolite was reduced to 11%, but not completely blocked, by MAO inhibition. This residual MPP+ production appeared to be iron-dependent since it was decreased (30 to 50%) by iron chelators, i.e., deferoxamine or phenanthroline, and was enhanced (by approximately 40%) in the presence of ADP-Fe3+. ADP-Fe3+ also enhanced the oxidation of MPTP to MPP+ which occurs in medium without cells. MPP+ formation, however, was significantly slower in plain culture medium than in astrocyte incubations pretreated with MAO inhibitors, suggesting the involvement of cells in these iron-mediated reactions. The data indicate that oxidation via MAO is the primary but not the only pathway of MPTP bioactivation and that transition metals may contribute to the generation of the toxic MPP+ metabolite in biological systems.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Ferric iron has been shown to participate in the conversion of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine into the toxic metabolite 1-methyl-4-phenylpyridinium ion.
“Ferric iron has been shown to participate in the conversion of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (a neurotoxin known to induce Parkinson’s disease-like symptoms) into the toxic metabolite 1-methyl-4-phenylpyridinium ion.68”
From The role of iron in brain ageing and neurodegenerative disorders (2014) · cites this paper as [68]
Cites
PROTEIN MEASUREMENT WITH THE FOLIN PHENOL REAGENT
Lowry, O. H., Rosebrough, N., Farr, A. L., & Randall, R. (1951) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)52451-6 · Cited by 315,771 · see citing works
Burns, R. S., Chiueh, C. C., Markey, S. P., Ebert, M. H., Jacobowitz, D. M., & Kopin, I. J. (1983) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.80.14.4546 · Cited by 2,149 · see citing works
Dexter, D. T., Wells, F. R., Lee, A. J., Agid, F., Agid, Y., Jenner, P., & Marsden, C. D. (1989) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.1989.tb07264.x · Cited by 1,149 · see citing works
Metabolism of the neurotoxic tertiary amine, MPTP, by brain monoamine oxidase
Chiba, K., Trevor, A. J., & Castagnoli, N. (1984) · Biochemical and Biophysical Research Communications · doi:10.1016/0006-291x(84)91293-2 · Cited by 1,098 · see citing works
Heikkila, R. E., Manzino, L., Cabbat, F. S., & Duvoisin, R. C. (1984) · Nature · doi:10.1038/311467a0 · Cited by 1,010 · see citing works
Intraneuronal generation of a pyridinium metabolite may cause drug-induced parkinsonism
Markey, S. P., Johannessen, J. N., Chiueh, C. C., Burns, R. S., & Herkenham, M. A. (1984) · Nature · doi:10.1038/311464a0 · Cited by 786 · see citing works
Pargyline Prevents MPTP-Induced Parkinsonism in Primates
Langston, J. W., Irwin, I., Langston, E. B., & Forno, L. S. (1984) · Science · doi:10.1126/science.6332378 · Cited by 581 · see citing works
Langston, J. W., Irwin, I., Langston, E. B., & Forno, L. S. (1984) · Neuroscience Letters · doi:10.1016/0304-3940(84)90293-3 · Cited by 435 · see citing works
An introduction to the free radical hypothesis in Parkinson's disease
Olanow, C. W. (1992) · Annals of Neurology · doi:10.1002/ana.410320703 · Cited by 382 · see citing works
Astrocytes convert the parkinsonism inducing neurotoxin, MPTP, to its active metabolite, MPP+
Ransom, B. R., Kunis, D. M., Irwin, I., & Langston, J. W. (1987) · Neuroscience Letters · doi:10.1016/0304-3940(87)90543-x · Cited by 209 · see citing works
Salach, J. I., Singer, T. P., Castagnoli, N., & Trevor, A. J. (1984) · Biochemical and Biophysical Research Communications · doi:10.1016/0006-291x(84)90614-4 · Cited by 198 · see citing works
Effects of metal chelating agents on the oxidation of lipids induced by copper and iron
Yoshida, Y., Furuta, S., & Niki, E. (1993) · Biochimica et Biophysica Acta (BBA) - Lipids and Lipid Metabolism · doi:10.1016/0005-2760(93)90052-b · Cited by 119 · see citing works
Ben‐Shachar, D., Eshel, G., Riederer, P. F., & Youdim, M. B. H. (1992) · Annals of Neurology · doi:10.1002/ana.410320718 · Cited by 95 · see citing works
Schipper, H. M. (1991) · Glia · doi:10.1002/glia.440040404 · Cited by 53 · see citing works
Monte, D. A. D., Wu, E. Y., Irwin, I., DeLanney, L. E., & Langston, J. W. (1991) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/s0022-3565(25)20491-8 · Cited by 52 · see citing works
Self-citationA catalyst function for MPTP in superoxide formation
Poirier, J., & Barbeau, A. (1985) · Biochemical and Biophysical Research Communications · doi:10.1016/0006-291x(85)90230-x · Cited by 49 · see citing works
Smith, M. T., Ekström, G., Sandy, M. S., & Monte, D. A. D. (1987) · Life Sciences · doi:10.1016/0024-3205(87)90301-8 · Cited by 35 · see citing works
Self-citationWu, E. Y., Langston, J. W., & Monte, D. A. D. (1992) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/s0022-3565(25)10739-8 · Cited by 28 · see citing works
Self-citationA high dose of MPTP overcomes the protective effect of selegiline against dopaminergic neurotoxicity
Fuller, R. W., & Hemrick-Luecke, S. K. (1989) · Journal of Pharmacy and Pharmacology · doi:10.1111/j.2042-7158.1989.tb06509.x · Cited by 9 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
The role of iron in brain ageing and neurodegenerative disorders
Ward, R. J., Zucca, F. A., Duyn, J. H., Crichton, R. R., & Zecca, L. (2014) · The Lancet Neurology · doi:10.1016/s1474-4422(14)70117-6 · Cited by 1,819 · see citing works
Heme oxygenase-1 and neurodegeneration: expanding frontiers of engagement
Schipper, H. M., Song, W., Zukor, H., Hascalovici, J. R., & Zeligman, D. (2009) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2009.06160.x · Cited by 298 · see citing works
Heme oxygenase expression in human central nervous system disorders
Schipper, H. M. (2004) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2004.09.015 · Cited by 237 · see citing works
Zecca, L., Casella, L., Albertini, A., Bellei, C., Zucca, F. A., Engelen, M., Żądło, A. C., Szewczyk, G. M., Zaręba, M., & Sarna, T. (2008) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2008.05541.x · Cited by 233 · see citing works
The sinister face of heme oxygenase-1 in brain aging and disease
Schipper, H. M., Song, W., Tavitian, A., & Cressatti, M. (2018) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2018.06.008 · Cited by 202 · see citing works
Brain iron deposition and the free radical-mitochondrial theory of ageing
Schipper, H. M. (2004) · Ageing Research Reviews · doi:10.1016/j.arr.2004.02.001 · Cited by 177 · see citing works
Nitti, M., Piras, S., Brondolo, L., Marinari, U. M., Pronzato, M. A., & Furfaro, A. L. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19082260 · Cited by 161 · see citing works
Astrocytes, brain aging, and neurodegeneration
Schipper, H. M. (1996) · Neurobiology of Aging · doi:10.1016/0197-4580(96)00014-0 · Cited by 138 · see citing works
Hamre, K., Tharp, R., Poon, K. K.-Y., Xiong, X., & Smeyne, R. J. (1999) · Brain Research · doi:10.1016/s0006-8993(99)01273-1 · Cited by 133 · see citing works
Heme Oxygenase‐1: Transducer of Pathological Brain Iron Sequestration under Oxidative Stress
Schipper, H. M. (2004) · Annals of the New York Academy of Sciences · doi:10.1196/annals.1306.007 · Cited by 117 · see citing works
Zukor, H., Song, W., Liberman, A., Mui, J., Vali, H., Fillebeen, C., Pantopoulos, K., Wu, T., Guerquin‐Kern, J., & Schipper, H. M. (2009) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2009.06007.x · Cited by 105 · see citing works
Astrocyte Modulation of Neurotoxic Injury
Aschner, M., Sonnewald, U., & Tan, K. H. (2002) · Brain Pathology · doi:10.1111/j.1750-3639.2002.tb00465.x · Cited by 100 · see citing works
Heme oxygenase in neuroprotection: from mechanisms to therapeutic implications
Chen, J. (2014) · Reviews in the Neurosciences · doi:10.1515/revneuro-2013-0046 · Cited by 85 · see citing works
Inoue, H., Castagnoli, K., der Schyf, C. V., Mabic, S., Igarashi, K., & Castagnoli, N. (1999) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/s0022-3565(24)35176-6 · Cited by 82 · see citing works
Metallobiology of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine neurotoxicity
Hare, D. J., Adlard, P. A., Doble, P. A., & Finkelstein, D. I. (2013) · Metallomics · doi:10.1039/c2mt20164j · Cited by 78 · see citing works
Guo, J., Yue, F., Song, D., Bousset, L., Liang, X., Tang, J., Yuan, L., Li, W., Melki, R., Tang, Y. C., et al. (2021) · Cell Death and Disease · doi:10.1038/s41419-020-03369-x · Cited by 74 · see citing works
Glial HO-1 expression, iron deposition and oxidative stress in neurodegenerative diseases
Schipper, H. M. (1999) · Neurotoxicity Research · doi:10.1007/bf03033339 · Cited by 72 · see citing works
El-Ghaiesh, S. H., Bahr, H. I., Ibrahiem, A. T., Ghorab, D. S., Alomar, S. Y., Farag, N. E., & Zaitone, S. A. (2020) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2020.00084 · Cited by 68 · see citing works
RetractedShi, L., Huang, C., Luo, Q., Xia, Y., Liu, W., Zeng, W., Cheng, A., Shi, R., & Zhengli, C. (2020) · Aging · doi:10.18632/aging.103225 · Cited by 64 · see citing works
Schildknecht, S., Pape, R., Meiser, J., Karreman, C., Strittmatter, T., Odermatt, M., Cirri, E., Friemel, A., Ringwald, M., Pasquarelli, N., et al. (2015) · Antioxidants and Redox Signaling · doi:10.1089/ars.2015.6297 · Cited by 60 · see citing works
Astrocyte Mitochondria: A Substrate for Iron Deposition in the Aging Rat Substantia Nigra
Schipper, H. M., Vininsky, R., Brull, R., Small, L., & Brawer, J. R. (1998) · Experimental Neurology · doi:10.1006/exnr.1998.6854 · Cited by 60 · see citing works
A Heme Oxygenase-1 Transducer Model of Degenerative and Developmental Brain Disorders
Schipper, H. M., & Song, W. (2015) · International Journal of Molecular Sciences · doi:10.3390/ijms16035400 · Cited by 57 · see citing works
Effects of cytisine on hydroxyl radicals in vitro and MPTP-induced dopamine depletion in vivo
Ferger, B., Spratt, C., Teismann, P., SEITZ, G., & Kuschinsky, K. (1998) · European Journal of Pharmacology · doi:10.1016/s0014-2999(98)00696-7 · Cited by 54 · see citing works
Astroglia overexpressing heme oxygenase‐1 predispose co‐cultured PC12 cells to oxidative injury
Song, L., Song, W., & Schipper, H. M. (2007) · Journal of Neuroscience Research · doi:10.1002/jnr.21367 · Cited by 51 · see citing works
Song, W., Cressatti, M., Zukor, H., Liberman, A., Galindez, C., & Schipper, H. M. (2017) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2017.06.017 · Cited by 50 · see citing works
Wong, S. S., Li, R. H. Y., & Stadlin, A. (1999) · Brain Research · doi:10.1016/s0006-8993(99)01661-3 · Cited by 45 · see citing works
Neonatal iron potentiates adult MPTP-induced neurodegenerative and functional deficits
Fredriksson, A., Schröder, N., Eriksson, P. O., Izquierdo, I., & Archer, T. (2001) · Parkinsonism & Related Disorders · doi:10.1016/s1353-8020(00)00028-6 · Cited by 42 · see citing works
Colafrancesco, V., & Villoslada, P. (2011) · PubMed · doi:10.4449/aib.v149i2.1376 · Cited by 41 · see citing works
Colín-González, A. L., Orozco‐Ibarra, M., Chánez‐Cárdenas, M. E., Rangel‐López, E., Santamarı́a, A., Pedraza‐Chaverrí, J., Barrera‐Oviedo, D., & Maldonado, P. D. (2012) · Neuroscience · doi:10.1016/j.neuroscience.2012.11.031 · Cited by 39 · see citing works
Significant up-regulation of nestin protein in the neostriatum of MPTP-treated mice
Chen, L.-W., Wei, L.-C., Qiu, Y., Liu, L., Rao, Z.-R., Ju, G., & Chan, Y. (2002) · Brain Research · doi:10.1016/s0006-8993(01)03253-x · Cited by 34 · see citing works
Jia, Z., Zhu, H., Li, Y., & Misra, H. P. (2009) · Neurochemical Research · doi:10.1007/s11064-009-9978-8 · Cited by 32 · see citing works
Royland, J. E., & Langston, J. W. (1998) · Humana Press eBooks · doi:10.1007/978-1-59259-477-1_6 · Cited by 26 · see citing works
The Role of Iron in Parkinson Disease and 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine Toxicity
Yantiri, F., & Andersen, J. K. (1999) · IUBMB Life · doi:10.1080/713803493 · Cited by 25 · see citing works
Bazmandegan, G., Zamanian, M. Y., Giménez‐Llort, L., Nikbakhtzadeh, M., Kamiab, Z., & Heidari, M. (2022) · Current Molecular Pharmacology · doi:10.2174/1874467215666220620143655 · Cited by 23 · see citing works
METALLOTHIONEINS AS EARLY AND SENSITIVE BIOMARKERS OF REDOX SIGNALING IN NEURODEGENERATIVE DISORDERS
Sharma, S. K., & Ebadi, M. (2011) · Cited by 16 · see citing works
St‐Jacques, R., Chapman, A., Lacaille, J., Mohr, G., & Schipper, H. M. (1999) · Neuroscience · doi:10.1016/s0306-4522(98)00487-4 · Cited by 11 · see citing works
Usuki, E., Bloomquist, J. R., Freeborn, E. R., Castagnoli, K., der Schyf, C. J. V., & Castagnoli, N. (2002) · Neurotoxicity Research · doi:10.1080/10298420290007628 · Cited by 9 · see citing works
Schipper, H. M., Small, L., Wang, X., & Brawer, J. R. (2002) · Developmental Neuroscience · doi:10.1159/000065692 · Cited by 9 · see citing works
Dysregulation of a Heme Oxygenase–Synuclein Axis in Parkinson Disease
Cressatti, M., & Schipper, H. M. (2022) · NeuroSci · doi:10.3390/neurosci3020020 · Cited by 6 · see citing works
Litvinenko, I., & Lobzin, V. Y. (2022) · Advances in Gerontology · doi:10.1134/s2079057022040117 · Cited by 5 · see citing works
Litvinenko, I., & Вячеславович, К. И. (2021) · Russian Military Medical Academy Reports · doi:10.17816/rmmar83609 · Cited by 2 · see citing works
Glial heme oxygenase-1 in CNSinjury and disease
Schipper, H. M. (2003) · Advances in molecular and cell biology · doi:10.1016/s1569-2558(03)31038-0 · Cited by 1 · see citing works
Brain Iron Deposition in Aging and Disease: Role of HO-1
Schipper, H. M. (2009) · Humana Press eBooks · doi:10.1007/978-1-59745-462-9_7 · Cited by 1 · see citing works
- Authors
- Di Monte, D. A., Schipper, H. M., Hetts, S., & Langston, J. W.
- Affiliations
- Jewish General Hospital (CA)
- Parkinson's Institute and Clinical Center (US)
- Venue
- Glia
- Publisher
- Wiley
- Published
- 1995-10
- Volume
- 15
- Issue
- 2
- Pages
- 203-206
- ISSN
- 0894-1491 (ISSN-L)
- 1098-1136
- OpenAlex
- W2170860545
- Cited by
- 43
- References
- 19
- Citations by year
- 2022: 3 · 2021: 2 · 2020: 2 · 2018: 2 · 2017: 1 · 2015: 2 · 2014: 2 · 2013: 1 · 2012: 1
- FWCI
- 1.20
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Glia (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Neuroscience › Neurology › Neurological diseases and metabolism
- Physical Sciences › Chemistry › Inorganic Chemistry › Metal-Catalyzed Oxygenation Mechanisms
- Keywords
- MPTP, MPP+, iron-mediated oxidation, astrocytes, monoamine oxidase inhibition, clorgyline, selegiline, iron chelators, deferoxamine, phenanthroline, neurotoxicity, transition metals, metabolic activation, Parkinson's disease
- MeSH terms
- Animals, Biotransformation, Cells, Cultured, Iron, Iron Chelating Agents, Monoamine Oxidase Inhibitors, Neuroglia, Dopamine Agents, 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine, 1-Methyl-4-phenylpyridinium, Prosencephalon, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
