Summary
The ability of 1-deprenyl to protect against the parkinsonian effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) has been attributed to the inhibition of conversion of MPTP to MPP+ (1-methyl-4-phenylpyridinium) catalyzed by MAO-B. We report here that deprenyl-treatment in mice has an additional neuroprotective element associated with the rapid metabolization of 1-deprenyl to 1-methamphetamine and 1-amphetamine. 1-Methamphetamine and 1-amphetamine inhibit MPP+-uptake into striatal synaptosomes prepared from rats. Post-treatment by 1-deprenyl, 1-methamphetamine, 1-amphetamine (at times when MPTP is no longer present in the striatum of mice) protects against neurotoxicity in C57BL mice by blocking the uptake of MPP+ into dopaminergic neurons, and even against the neurotoxicity induced by 2’CH3-MPTP, which is partly bioactivated by MAO-A. These findings may have clinical implications since deprenyl has recently been found to delay the progression of Parkinson’s disease.
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References
Birkmayer W, Knoll J, Riederer P, Youdim MBH, Hars V, Marton J (1985) Increased life expectancy resulting from addition of 1-deprenyl to MadoparR treatment in Parkinson’s disease: a longterm study. J Neural Transm 64: 113–127.
Birkmayer W, Riederer P, Ambrozi L, Youdim MBH (1977) Implications of combined treatment with Madopar and L-deprenyl in Parkinson’s disease. Lancet i: 439–443.
Brooks WJ, Jarvis MF, Wagner GC (1989) Astrocytes as a primary locus for the conversion of MPTP into MPP+. J Neural Transm 76: 1–12.
Chiba K, Trevor A, Castagnoli N (1984) Metabolism of the neurotoxic tertiary amine, MPTP, by brain monoamine oxidase. Biochem Biophys Res Commun 120: 574–578.
Chiueh CC, Johannessen JN, Sun JL, Bacon JP, Markey SP (1986) Reversible neuro-toxicity of MPTP in the nigrostriatal dopaminergic system of mice. In: Markey SP, Castagnoli N Jr, Trevor AJ, Kopin IJ (eds) MPTP — a neurotoxin producing a parkinsonian syndrome. Academic Press, New York, pp 473–479.
Cohen G, Pasik P, Cohen B, Leist A, Mytilineneou C, Yahr MD (1984) Pargyline and deprenyl prevent neurotoxicity of 1-methyl-4-phenyl-1,2,3,4-tetrahydropiridine (MPTP) in monkeys. Eur J Pharmacol 106: 209–210.
Davis GC, Williams AC, Markey SP, Ebert MH, Caine ED, Reichert CM, Kopin IJ (1979) Chronic Parkinsonism secondary to intravenous injection of meperidine analogs. Psychiatry Res 1: 249–254.
Dudley MW (1988) The depletion of rat cortical norepinephrine and the inhibition of [3H]-norepinephrine uptake by xylamine does not require monoamine oxidase activity. Life Sci 43: 1871–1877.
Finnegan KT, Skratt JJ, Irwin I, DeLanney LE, Langston JW (1990) Protection against DSP-4-induced neurotoxicity by deprenyl is not related to its inhibition of MAO-B. Eur J Pharmacol 184: 119–126.
Hallman H, Olsen L, Jonsson G (1984) Neurotoxicity of the meperidine analogue N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine on brain catecholamine neurons in the mouse. Eur J Pharmacol 97: 133–136.
Heikkila RE, Hess A, Duvoisin RC (1984) Dopaminergic neurotoxicity of 1-methyl-4-phenyl-1,2,3,4-tetrahydropiridine in mice. Science 224: 1451–1453.
Heikkila RE, Manzino L, Cabbat FS, Duvoisin RC (1984) Protection against the dopaminergic neurotoxicity of 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine by monoamine oxidase inhibitors. Nature 311: 467–469.
Horn AS (1978) Characteristics of neuronal dopamine uptake. In: Roberts PJ (ed) Advances in biochemical psychopharmacology, vol 19. Raven Press, New York, pp 25–34.
Heikkila RE, Sonsalla PK (1987) The use of the MPTP-treated mouse as an animal model of parkinsonism. Can J Neurol Sci 14: 436–440.
Javitch JA, D’Amato RJ, Strittmatter SM, Snyder SH (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. Proc Natl Acad Sci USA 82: 2173–2177.
Javitch JA, Snyder SH (1985) Uptake of MPP+ by dopamine neurons explains selectivity of parkinsonism inducing neurotoxin, MPTP. Eur J Pharmacol 106: 455–456.
Jonsson G, Sundström E, Nwanze E, Hallman H, Luthman J (1986) Mode of action of MPTP on catecholominergic neurons in the mouse. In: Markey SP, Castagnoli N Jr, Trevor AJ, Kopin IJ (eds) MPTP — a neurotoxin producing a parkinsonian syndrome. Academic Press, New York, pp 253–272.
Karoum F, Chuang LW, Eisler T, Calne DB, Liebowitz MR, Quitkin FM, Klein DF, Wyatt RJ (1982) Metabolism of (-)-deprenyl to amphetamine and metamphetamine may be responsible for deprenyl’s therapeutic benefit: a biochemical assessment. Neurology 32: 503–509.
Knoll J (1978) The possible mechanism of action of (-)-deprenyl in Parkinson’s disease. J Neural Transm 43: 177–198.
Langston JW, Ballard P, Tetrud JW, Irwin I (1983) Chronic parkinsonism in humans due to a product of meperidine-analog synthesis. Science 219: 979–980.
Langston JW, Irwin I, Langston EB, Forno LS (1984) Pargyline prevents MPTP-induced parkinsonism in primates. Science 225: 1480–1482.
Li X-M, Juorio AV, Paterson IA, Meng-Yang Z, Boulton AA (1992) Specific irreversible monoamine oxidase B inhibitors stimulate gene expression of aromatic 1-amino acid decarboxylase in PC12 cells. J Neurochem 59: 2324–2327.
Markey SP, Johannessen JN, Chiueh CC, Burns RS, Herkenham MA (1984) Intra-neuronal generation of a pyridinium metabolite may cause drug-induced parkinsonism. Nature 311: 464–467.
Mayer RA, Kindt MV, Heikkila RE (1986) Prevention of the nigrostriatal toxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine by inhibitors of 3,4-dihydroxy-phenylethyl-amine transport. J Neurochem 47: 1073–1079.
Mytilineou C, Cohen G (1984) 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine destroys dopamine neurons in expiants of rat embryo mesencephalon. Science 225: 529–531.
Mytilineou C, Cohen G (1985) Deprenyl protects dopamine neurons from the neuro-toxic effect of 1-methyl-4-phenyl pyridinium ion. J Neurochem 45: 1951–1953.
Parkes JD, Tarsy D, Marsden CD, Bovili KT, Phipps JA, Rose P, Asselman P (1975) Amphetamines in the treatment of Parkinson’s disease. J Neurol Neurosurg Psychiatry 38: 232–237.
Parkinson Study Group (1989) Effect of deprenyl on the progression of disability in early Parkinson’s disease. N Engl J Med 321: 1364–1371.
Patthy M, Gyenge R (1988) Perfluorinated acids as ion-pairing agent in the determination of monoamine transmitters and some prominent metabolites in rat brain by high-performance liquid chromatography with amperometic detection. J Chromatogr 449: 191–205.
Philips RS (1981) Amphetamine, parahydroxy-amphetamine and beta-phenylethylamine in mouse brain and urine after (—)-and (+)-deprenyl administration. J Pharm Pharmacol 33: 739–741.
Reynolds GP, Elsworth JD, Blau K, Sandier M, Lees AJ, Stern GM (1978) Deprenyl is metabolized to methamphetamine and amphetamine in man. Br J Clin Pharmacol 6: 542–544.
Schacht U, Heptner W (1974) Effect of nomiphensine (HOE 984), a new antidepressant on uptake of noradrenaline and serotonin and on release of noradrenaline in rat brain synaptosomes. Biochem Pharmacol 23: 3413–3422.
Sershen H, Mason MF, Reith MEA, Hashim A, Lajtha A (1986) Effect of amphetamine on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxicity in mice. Neuropharmacology 25: 927–930.
Sershen H, Mason MF, Reith MEA, Hashim A, Lajtha A (1986) Effect of nicotine and amphetamine N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxicity in mice. Neuropharmacology 25: 1231–1234.
Sonsalla DK, Yougster SK, Kindt MV, Heikkila RE (1987) Characteristics of 1-methyl-4-(2’methylphenyl)-1,2,3,6-tetrahydropyridine-induced neurotoxicity in the mouse. J Pharmacol Exp Ther 242: 850–857.
Sundström E, Jonsson G (1986) Differential time course of protection by monoamine oxidase inhibition and uptake inhibition against MPTP neurotoxicity on central catecholamine neurons in mice. Eur J Pharmacol 122: 275–278.
Sziráki I, Andrási F, Berzsenyi P, Horváth K, Kardos V, Patthy M, Pátfalusi M, Szabó G, Szabó H (1990) Pharmacological and neurochemical properties of GYKI-52 895, a new selective dopamine uptake inhibitor. In: Abstracts of Dopamine’ 90. Satellite Meeting of the XIth International Congress of Pharmacology, Como, Italy, July 8–11, 1990, p 36.
Sziráki I, Kardos V, Patthy M, Pátfalusi M, Budai Gy (1993) Methamphetamine protects against MPTP-neurotoxicity in mice C57BL. Eur J Pharmacol (submitted).
Tatton WG, Greenwood CE (1991) Rescue of dying neurons: a new action for deprenyl in MPTP parkinsonism. J Neurosci Res 30: 666–672.
Tetrud JW, Langston JW (1989) The effect of deprenyl (selegiline) on the natural history of Parkinson’s disease. Science 245: 519–522.
Wurtman RJ, Axelrod J (1963) A sensitive and specific assay for the estimation of monoamine oxidase. Biochem Pharmacol 12: 1439–1440.
Youngster SK, Duvoisin RC, Hess A, Sonsalla PK, Kindt MV, Heillika RE (1986) 1-methyl-4-(2’-methylphenyl)-1,2,3,6-tetrahydropyridine (2’-CH3-MPTP) is a more potent dopaminergic neurotoxin than MPTP in mice. Eur J Pharmacol 122: 283–287.
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© 1994 Springer-Verlag
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Sziráki, I. et al. (1994). Amphetamine-metabolites of deprenyl involved in protection against neurotoxicity induced by MPTP and 2′-methyl-MPTP. In: Tipton, K.F., Youdim, M.B.H., Barwell, C.J., Callingham, B.A., Lyles, G.A. (eds) Amine Oxidases: Function and Dysfunction. Journal of Neural Transmission, vol 41. Springer, Vienna. https://doi.org/10.1007/978-3-7091-9324-2_27
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DOI: https://doi.org/10.1007/978-3-7091-9324-2_27
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