Abstract
Just 4 years ago there were few if any hints of a connection between pyridines and Parkinson’s disease. Yet a current review, particularly one focusing on experimental models, would be flawed without a discussion of this newly discovered relationship. This striking turn of events has been precipitated almost entirely by the discovery of a single compound, l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine, or, as it is now widely know, MPTP. In this chapter, we will explore the relevance of this compound and other pyridines to Parkinson’s disease. As should become clear, investigations into the biologic effects of these “pyridine neurotoxins” have provided a surprising number of research avenues, ranging from the development of new animal models for the disease, to a serious reassessment of etiologic factors.
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References
Ambani LM, Van Woert MH, Murphy S (1975) Brain peroxidase and catalase in Parkinson disease. Arch Neurol 32: 114–118
Arai Y, Kinemuchi H, Hamamichi N, Satoh N, Tadano T, Kisara K (1986) Inhibition of rat brain monoamine oxidase by some analogues of l-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and l-methyl-4-phenylpyridinium ion. Neurosci Lett 66: 43–48
Ballard PA, Tetrud JW, Langston JW (1985) Permanent human parkinsonism due to l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP): seven cases. Neurology (NY) 35: 949–956
Barbeau A, Roy M, Langston JW (1985) Neurological consequence of industrial exposure to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Lancet 1: 747
Barbeau A, Dallaire L, Buu NT, Veilleux F, Boyer H, DeLanney LE, Irwin I, Langston EB, Langston JW (1986 a) New amphibian models for the study of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Life Sci 36: 1125–1134
Barbeau A, Poirier J, Dallaire L, Rucinska E, Buu NT, Donaldson J (1986b) Studies on MPTP, MPP+ and paraquat in frogs and in vitro. In: Markey SP, Castagnoli N Jr, Trevor AJ, Kopin IJ (eds) MPTP: a neurotoxin producing a parkinsonian syndrome. Academic, New York, p 85–103
Barnes RA (1960) Properties and reactions of pyridine and its hydrogenated derivatives. In: Klingsbert E (ed) Pyridine and derivatives, part 1. InterScience, New York, p 1–97
Baumann RJ, Jameson HD, McKean HE, Haack DG, Weisberg LM (1980) Cigarette smoking and Parkinson disease: 1. A comparison of cases with matched neighbors. Neurology (NY) 30: 839–843
Beal MF, Kowall NW, Ellison DW, Mazurek MF, Swartz KJ, Martin JB (1986) Replication of the neurochemical characteristics of Huntington’s disease by quinolinic acid. Nature 321: 169–171
Benedetti MS, Keane PE (1980) Differential changes in monoamine oxidase A and B activity in the aging rat brain. J Neurochem 35: 1026–1032
Blakemore WF (1980) Isoniazid. In: Spencer PS, Schaumburg HH (eds) Experimental and clinical neurotoxicology. Williams and Wilkins, Baltimore, pp 476–489
Boyce S, Kelly E, Reavill C, Jenner P, Marsden CD (1984) Repeated administration of N-methyl-4-phenyl-l,2,5,6-tetrahydropyridine to rats is not toxic to striatal dopamine neurons. Biochem Pharmacol 33: 1747–1752
Bradbury AJ, Brossi A, Costall B, Domeney AM, Gessner W, Naylor RJ (1986) Biochemical changes caused by the infusion into the substantia nigra of the rat of MPTP and related compounds which antagonise dihydropteridine reductase. Neuropharmacology 25 (6): 583–586
Brody F, Ruby (1960) Synthetic and natural sources of the pyridine ring. In: Klingsbert E (ed) Pyridine and derivatives, part 1. InterScience, New York, p 99–589
Burns RS, Chiueh CC, Markey SP, Ebert MH, Jacobowitz DM, Kopin IJ (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. Proc Natl Acad Sci USA 80: 4546–4550
Carvey PM, Kao LC, Klawans HL (1986) Permanent postural effects of MPTP in the guinea pig. In: Markey SP, Castagnoli N Jr, Trevor AJ, Kopin IJ (eds) MPTP: a neurotoxin producing a parkinsonian syndrome. Academic, New York, p 407–411
Chiba K, Trevor A, Castagnoli N Jr (1984) Metabolism of the neurotoxic tertiary amine, MPTP, by brain monoamine oxidase. Biochem Biophys Res Commun 120: 574–578
Chiba K, Peterson LA, Castagnoli KP, Trevor AJ, Castagnoli N Jr (1985 a) Studies on the molecular mechanism of bioactivation of the selective nigrostriatal toxin 1-methyl-4-phenyl-l,2,3,6-tetrahydropyridine. Drug Metab Dispos 13: 342–347
Chiba K, Trevor AJ, Castagnoli N Jr (1985b) Active uptake of MPP+, a metabolite of MPTP, by brain synaptosomes. Biochem Biophys Res Commun 128: 1229–1232
Chiueh CC, Markey SP, Burns RS, Johannessen JN, Jacobowitz DM, Kopin IJ (1984 a) Selective neurotoxic effects of N-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP) in subhuman primates and man: a new animal model of Parkinson’s disease. Psychopharmacol Bull 20: 548–553
Chiueh CC, Markey SP, Burns RS, Johannessen J, Pert A, Kopin IJ (1984b) Neurochemical and behavioral effects of systemic and intranigral administration of N-methyl-4-phenyl-l,2,3,6-tetrahydropyridine in the rat. Eur J Pharmacol 100: 189–194
Cohen G, Pasik P, Cohen B, Leist A, Mytilineou C, Yahr MD (1985) Pargyline and deprenyl prevent the neurotoxicity of l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP) in monkeys. Eur J Pharmacol 106: 209–210
Cote LJ, Kremzner LT (1983) Biochemical changes in normal aging in human brain. In: Mayeux R, Rosen WG (eds) The dementias. Raven, New York, p 19–30
D’Amato RJ, Lipman ZP, Snyder SH (1986) Selectivity of the parkinsonian neurotoxin MPTP: toxic metabolite MPP+ binds to neuromelanin. Science 231: 987–989
D’Amato RJ, Alexander GM, Schwartzman RJ, Kitt CA, Price DL, Snyder SH (1987) Molecular mechanisms of MPTP-induced toxicity. II. Neuromelanin: a role in MPTP-induced neurotoxicity. Life Sci 40: 705–712
DeLanney LE, Ricaurte GA, Irwin I, Forno LS, Langston JW (1986) Neurotoxicity of MPTP varies depending on the route of administration (abstract). Soc Neurosci 12: 90
Finnegan KT, Irwin I, DeLanney LE, Ricaurte GA, Langston JW (1987) 1,2,3,6-Tetrahydro-l-methyl-4-(methylpyrrol-2-yl)pyridine: studies on the mechanism of action of l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine. J Pharmacol Exp Ther 242: 1144–1151
Forno LS, DeLanney LE, Irwin I, Langston JW ( 1986 a) Neuropathology of MPTP-treated monkeys: comparison with the neuropathology of human idiopathic Parkinson’s disease. In: Markey SP, Castagnoli N Jr, Trevor AJ, Kopin IJ (eds) MPTP: a neurotoxin producing a parkinsonian syndrome. Academic, New York, p 119–140
Forno LS, Langston JW, DeLanney LE, Irwin I, Ricaurte GA (1986 b) Locus ceruleus lesions and eosinophilic inclusions in MPTP-treated monkeys. Ann Neurol 20: 449–455
Fries DS, de Vries J, Hazelhoff B, Horn AS (1986) Synthesis and toxicity toward nigrostriatal dopamine neurons of l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP) analogues. J Med Chem 29 (3): 424–427
Fuller RW, Hemrick-Luecke SK (1985) Effects of amfonelic acid, α-methyltyrosine, RO 4-1284 and haloperidol pretreatment on the depletion of striatal dopamine by l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine in mice. Res Commun Chem Pathol Pharmacol 48: 17–25
Fuller RW, Hemrick-Luecke SK (1986)Persistent depletion of striatal dopamine in mice by M-hydroxy-MPTP. Res Commun Chem Pathol Pharmacol 53(2): 167–172
Gupta M, Gupta BK, Thomas R, Bruemmer V, Sladek JR Jr, Felten DL (1986) Aged mice are more sensitive to l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine treatment than young adults. Neurosci Lett 70: 326–331
Hallman H, Olson L, Jonsson G (1084) Neurotoxicity of the meperidine analogue N-methyl-4-phenyl-l,2,3,6-tetrahydropyridine on brain catecholamine neurons in the mouse. Eur J Pharmacol 97: 133–136
Hallman H, Lange J, Olson L, Stromberg I, Jonsson J (1985) Neurochemical and histochemical characterization of neurotoxic effects of l-methyl-4-phenyl-l,2,3,6-tetra-hydropyridine on brain catecholamine neurons in the mouse. J Neurochem 44: 117–127
Heckman RA, Best FW (1981) An investigation of the lipophilic bases of cigarette smoke condensate. Tobacco Int 33: 83–89
Heikkila RE, Hess A, Duvoisin RC (1984 a) Dopaminergic neurotoxicity of 1-methyl-4-phenyl-l,2,5,6-tetrahydropyridine in mice. Science 224: 1451–1453
Heikkila RE, Manzino L, Cabbat FS, Duvoisin RC (1984b) Protection against the dop-aminergic neurotoxicity of l-methyl-4-phenyl-l,2,5,6-tetrahydropyridine by monoamine oxidase inhibitors. Nature 311: 467–469
Herken H, Lange K, Kolbe H (1969) Brain disorders induced by pharmacological blockade of the pentose phosphate pathway. Biochem Biophys Res Commun 36 (1): 93–100
Huy PTB, Meulemans A, Wassef M, Manuel C, Sterkers O, Amiel C (1983) Gentamicin persistence in rat endolymph and perilymph after a two-day constant infusion. Antimicrob Agents Chemother 23: 344–346
Irwin I (1986) The neurotoxin l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP):a key to Parkinson’s disease? Pharm Res 3: 7–11
Irwin I, Langston JW (1985) Selective accumulation of MPP+ in the substantia nigra: a key to neurotoxicity? Life Sci 36: 207–212
Irwin I, Langston JW, DeLanney LE (1987) 4-Phenylpyridine (4PP) and MPTP: the relationship between striatal MPP+ concentrations and neurotoxicity. Life Sci 40(8):731–740
Jacobowitz DM, Burns RS, Chiueh CC, Kopin IJ (1984) N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) causes destruction of the nigrostriatal but not the mesolimbic dopamine system in the monkey. Psychopharmacol Bull 20: 416–422
Jarvis MF, Wagner GC (1985) Neurochemical and functional consequences following l-methyl-4-phenyl-l,2,5,6-tetrahydropyridine (MPTP) and methamphetamine. Life Sci 36: 249–254
Javitch JA, D’Amato RJ, Strittmatter SM, Snyder SH (1985) Parkinsonism-inducing neurotoxin, N-methyl-4-phenyl-l,2,3,6-tetrahydropyridine: uptake of the metabolite N-methyl-4-phenylpyridine by dopamine neurons explains selective toxicity. Proc Natl Acad Sci USA 82: 2173–3177
Jenner P, Nadia MJ, Rupniak SR, Kelly E, Kilpatrick G, Lees A, Marsden CD (1984) l-Methyl-4-phenyl-l,2,3,6-tetrahydropyridine-induced parkinsonism in the common marmoset. Neurosci Lett 50: 85–90
Johannessen JN, Savitt JM, Markey CJ, Bacon JP, Weisz A, Hanselman DS, Markey SP (1987) Molecular mechanisms of MPTP-induced toxicity. I. The development of amine substituted analogues of MPTP as unique tools for the study of MPTP toxicity and Parkinson’s disease. Life Sci 40: 697–704
Kalaria RN, Mitchel MJ, Harik SI (1986) Blood-brain barrier monoamine oxidase: [3H] pargyline binding to cerebral microvessels (abstract). Soc Neurosci 11 (2): 1260
Kessler II, Diamond EL (1971) Epidemiologic studies of Parkinson’s disease. III. A community-based survey. Am J Epidemiol 96: 242–254
Langston JW (1985 a) MPTP and Parkinson’s disease. Trends Neurosci 80:79–83
Langston JW (1985 b) Mechanism of MPTP toxicity: more answers, more questions. TIPS 6:375–378
Langston JW, Ballard PA (1983) Parkinson’s disease in a chemist working with 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP). N Engl J Med 309: 310
Langston JW, Ballard PA (1984) Parkinsonism induced by l-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP): implications for treatment and the pathogenesis of Parkinson’s disease. Can J Neurol Sci 11: 160–165
Langston JW, Irwin I (1986) MPTP: current concepts and controversies. Clin Neuropharmacol 9: 485–507
Langston JW, Ballard PA, Tetrud JW, Irwin I (1983) Chronic parkinsonism in humans due to a product of meperidine-analog synthesis. Science 219: 979–980
Langston JW, Forno LS, Rebert CS, Irwin I (1984 a) Selective nigral toxicity after systemic administration of l-methyl-4-phenyl-l,2,5,6-tetrahydropyridine (MPTP) in the squirrel monkey. Brain Res 292: 390–394
Langston JW, Irwin I, Langston EB, Forno LS (1984b) l-Methyl-4-phenylpyridinium ion (MPP+): identification of a metabolite of MPTP, a toxin selective to the substantia nigra. Neurosci Lett 48: 87–92
Langston JW, Irwin I, Langston EB, Forno LS (1984 c) Pargyline prevents MPTP-induced parkinsonism in primates. Science 225: 1480–1482
Langston JW, Irwin I, Langston EB, Forno LS (1984d) The importance of the 4–5 double bond for neurotoxicity in primates of the pyridine derivative MPTP. Neurosci Lett 50: 289–294
Langston JW, Irwin I, DeLanney LE (1987) The biotransformation of MPTP and disposition of MPP+: the effects of aging. Life Sci 40 (8): 749–754
Langston JW, Irwin I, Ricaurte G (1987) Neurotoxins, parkinsonism and Parkinson’s disease. Pharmacol Ther 32: 19–49
Lent CM (1986) MPTP depletes neuronal monoamines and impairs the behavior of the medicinal leech. In: Markey SP, Castagnoli N Jr, Trevor AJ, Kopin IJ (eds) MPTP: a neurotoxin producing a parkinsonian syndrome. Academic, New York, pp 105–118
Lewin R (1986) Age factors loom in parkinsonian research. Science 234: 1200–1201
Loos D, Halbhubner K, Kehr W, Herken H (1977) Action of dopamine agonists on Parkinson-like muscle rigidity induced by 6-aminonicotinamide. NeuroScience 4: 667–676
Lyden A, Bondesson U, Larsson BS, Lindquist NG (1983) Melanin affinity of 1-methyl-4-phenyl-l,2,5,6-tetrahydropyridine, an inducer of chronic parkinsonism in humans. Acta Pharmacol Toxicol (Copenh) 53 (5): 429–432
Mann DMA, Yates PO (1983) Possible role of neuromelanin in the pathogenesis of Parkinson’s disease. Mech Ageing Dev 21: 193–203
Markey SP, Johannessen JN, Chiueh CC, Burns RS, Herkenham MA (1984) Intraneuronal generation of a pyridinium metabolite may cause drug-induced parkinsonism. Nature 311: 464–467
Marsden CD (1961) Pigmentation in the nucleus substantiae nigrae of mammals. J Anat 95 (2): 256–261
Melamed E, Rosenthal J, Clobus M, Cohen O, Frucht Y, Uzzan A (1985 a) Mesolimbic dopaminergic neurons are not spared by MPTP neurotoxicity in mice. Eur J Pharmacol 114: 970–1000
Melamed E, Rosenthal J, Cohen O, Globus M, Uzzan A (1985 b) Dopamine but not norepinephrine or serotonin uptake inhibitors protect mice against neurotoxicity of MPTP. Eur J Pharmacol 116: 179–181
Mytilineou C, Cohen G (1985) l-Methyl-4-phenyl-l,2,3,6-tetrahydropyridine destroys dopamine neurons from the neurotoxic effect of l-methyl-4-phenylpyridinium ion. J Neurochem 45: 1951–1953
Nefzger MD, Quadfasel FA, Karl VC (1968) A retrospective study of smoking and Parkinson’s disease. Am J Epidemiol 88: 149–158
Nicklas WJ, Vyas I, Heikkila RE (1985) Inhibition of NADH-linked oxidation in brain mitochondria by l-methyl-4-phenylpyridine, a metabolite of the neurotoxin, 1-methyl-4-phenyl-l,2,3,6-tetrahydropyridine. Life Sci 36: 2503–2508
Nicklas WJ, Youngster SK, Kindt MV, Heikkila RE (1987) MPTP, MPP+ and mitochondrial function. Life Sci 40: 721–729
Parisi JE, Burns RS (1986) The neuropathology of MPTP-induced parkinsonism in man and experimental animals. In: Markey SP, Castagnoli N Jr, Trevor AJ, Kopin IJ (eds) MPTP: a neurotoxin producing a parkinsonian syndrome. Academic, New York, p 141–148
Perry TL, Yong VW, Ito M, Jones K, Wall RA, Foulks JG, Wright JM, Kish SJ (1985) l-Methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP) does not destroy nigrostriatal neurons in the scorbutic guinea pig. Life Sci 36: 1233–1238
Ransom BR, Kunis DM, Irwin I, Langston JW (1987) Astrocytes convert the parkinsonism inducing neurotoxin, MPTP, to its active metabolite, MPP+. Neurosci Lett 75: 323–328
Ricaurte GA, Langston JW, DeLanney LE, Irwin I, Brooks JD (1985) Dopamine up-take blockers protect against the dopamine depleting effect of l-methyl-4-phenyl- 1,2,3,6-tetrahydropyridine (MPTP) in the mouse striatum. Neurosci Lett 59: 259–264
Ricaurte GA, Langston JW, DeLanney LE, Irwin I, Peroutka SJ, Forno LS (1986) Fate of nigrostriatal neurons in young mature mice given l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP): a neurochemical and morphological reassessment. Brain Res 376 (1): 117–124
Ricaurte GA, Irwin I, Forno LS, DeLanney LE, Langston EB, Langston JW (1987) Aging and MPTP-induced degeneration of dopaminergic neurons in the substantia nigra. Brain Res 403: 43–51
Robinson DS, Nies A, Davis JN, Bunney WE, Davis JM, Colburn RW, Bourne HR, Shaw DM, Coppen AJ (1972) Ageing, monoamines and monoamine-oxidase levels. Lancet 1: 290–291
Sahenk Z, Mendell JR (1980) Zinc pyridinethione. In: Spencer PS, Schaumburg HH (eds) Experimental and clinical neurotoxicology. Williams and Wilkins, Baltimore, pp 578–592
Sahgal A, Andrews JS, Biggins JA, Candy JM, Edwardson JA, Keith AB, Turner JD, Wright C (1984) N-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP) affects locomotor activity without producing a nigrostriatal lesion in the rat. Neurosci Lett 48: 179–184
Sayre LM, Arora PK, Iacofano LA, Harik SI (1986) Comparative toxicity of MPTP, MPP+ and 3,3-dimethyl-MPDP+ to dopaminergic neurons of the rat substantia nigra. Eur J Pharmacol 124: 171–174
Schneider JS, Markham CH (1986) Neurotoxic effects of N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in the cat. Tyrosine hydroxylase immunohistochemistry. Brain Res 373: 258–267
Schneider JS, Yuwiler A, Markham CH (1986) Production of a Parkinson-like syndrome in the cat with N-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP): behavior, histology, and biochemistry. Exp Neurol 91: 290–307
Snyder SH, D’Amato RJ (1986) MPTP: a neurotoxin relevant to the pathophysiology of Parkinson’s disease. Neurology (NY) 36: 250–258
Steranka LR, Polite LN, Perry KW, Fuller RW (1983) Dopamine depletion in rat brain by MPTP (l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine). Res Commun Substances Abuse 4: 315–323
Sundstrom E, Jonsson G (1985) Pharmacological interference with the neurotoxic action of l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP) on central catecholamine neurons in the mouse. Eur J Pharmacol 110: 293–299
Tetrud JW, Langston JW, Redmond DE, Roth RH, Sladek JR, Angel RW (1986) MPTP-induced tremor in human and non-human primates. Neurology (NY) 36 (Suppl 1): 308
Trevor AJ, Castagnoli N Jr, Caldera P, Ramsay RR, Singer TP (1987) Bioactivation of MPTP: reactive metabolites and possible biochemical sequelae. Life Sci 40: 713–719
Uhl GR, Javitch JA, Snyder SH (1985) Normal MPTP binding in parkinsonian substantia nigra: evidence for extraneuronal toxin conversion in human brain. Lancet 2: 956–957
Ward CD, Duvoisin RC, Ince SE, Nutt JD, Eldridge R, Calne DB (1983) Parkinson’s disease in 65 pairs of twins and in a set of quadruplets. Neurology (NY) 33: 815–824
Wilson JS, Wilson JA (1986) Intracellular recordings in the caudate nucleus of normal and MPTP treated dogs. In: Markey SP, Castagnoli N Jr, Trevor AJ, Kopin IJ (eds) MPTP: a neurotoxin producing a parkinsonian syndrome. Academic, Orlando, pp 695–699
Youngster SK, Duvoisin RC, Hess A, Sonsalla PK, Kindt MV, Heikkila RE (1986) l-Methyl-4-phenyl-(2′-methylphenyl)-l,2,3,6-tetrahydropyridine [2′CH3MPTP] is a more potent dopamine neurotoxin than MPTP in mice. Eur J Pharmacol 122: 283–287
Ziering A, Berger L, Heineman SD, Lee J (1947) Piperidine derivatives. Part III. 4-Ayrlpiperidines. J Org Chem 12: 894–903
Zimmerman DM, Cantrell BE, Reel JK, Hemrick-Luecke SK, Fuller RW (1986) Characterization of the neurotoxic potential of m-methoxy-MPTP and the use of its n-ethyl analogue as a means of avoiding exposure to a possible parkinsonism-causing agent. J Med Chem 29: 1517–1520.
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Langston, J.W., Irwin, I. (1989). Pyridine Toxins. In: Calne, D.B. (eds) Drugs for the Treatment of Parkinson’s Disease. Handbook of Experimental Pharmacology, vol 88. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-73899-9_7
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