Summary
The metabolism and the effects of L-threo-3,4-dihydroxyphenylserine (L-threo-DOPS) were studied in the rat brain striatum by in vivo microdialysis. In the brain L-threo-DOPS was metabolized by 3 different enzymes; aromatic L-amino acid decarboxylase, catechol-O-methyltransferase, and DOPS-aldolase. DOPS-aldolase was the main enzyme which metabolizes L-threo-DOPS. The amounts of the metabolites by L-amino acid decarboxylase (norepinephrine and its metabolites) were 0.4% of the total amounts of metabolites detected in the dialysate, while those by catechol-O-methyltransferase, 2.1%, and by DOPS-aldolase, 97.5%, after 100 min perfusion of L-threo-DOPS. L-threo-DOPS was found to increase extracellular levels of dopamine and serotonin, and to inhibit monoamine catabolism in the brain. Inhibition of DOPS-aldolase should improve its effectiveness as the supplement therapy of norepinephrine.
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Bartholini G, Constantinidis J, Puig M, Tissot R, Pletsher A (1975) The stereoisomers of 3,4-dihydroxyphenylserine as precursors of norepinephrine. J Pharmacol Exp Ther 193: 523–532
Bonnet A-M, Loria Y, Saint-Hilaire M-H, Lhermitte F, Agid Y (1987) Does long-term aggravation of Parkinson's disease result from nondopaminergic legions? Neurology 37: 1539–1542
Brennan T, Bhardwaj A, Yahr MD (1990) L-Threodops increases extracellular norepinephrine levels in the brain: an in vivo study. Neurology 40: 1134–1135
Bruns FH, Fiedler L (1958) Enzymatic cleavage and synthesis of L-threo-ψ-phenylserine and L-erythro-ψ-phenylserine. Nature 181: 1533
Coyle JT, Henry D (1973) Catechllamine in fetal and newborn rat brain. J Neurochem 21: 61–67
Creveling CR, Daly J, Tokuyama T, Witkop B (1968) The combined use of α-methyltyrosine and threo-dihydroxyphenylserine-in the central nervous system. Biochem Pharmacol 17: 65–70
Goodwin BL, Johnson RD, Leask BGS, Ruthven CRJ, Sandler M (1972) Threo-3,4-dihydroxyphenylserine, a poor source of noradrenaline in the rat. Experientia 28: 1298–1299
Ichinose H, Kojima K, Togari A, Kato Y, Parvez S, Parvez P, Nagatsu T (1985) Simple purification of aromatic L-amino acid decarboxylase from human pheochromocytoma using high-performance liquid chromatography. Anal Biochem 150: 3051–3057
Kato T, Karai N, Katsuyama M, Nakamura M, Katsube J (1987) Studies on the activity of L-threo-3,4-dihyroxyphenylserine (L-DOPS) as a catecholamine precursor in the brain comparison with that of L-DOPA. Biochem Pharmacol 36: 3051–3057
Maruyama W, Nakahara D, Ota M, Takahashi T, Takahashi A, Nagatsu T, Naoi M (1992) N-Methylation of dopammine-derived 6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline, (R)-salsolinol, in rat brains: in vivo microdialysis study. J Neurochem 59: 395–400
Maruyama W, Nakahara D, Dostert P, Hashiguchi H, Ohta S, Hirobe M, Takahashi A, Nagatsu T, Naoi M (1993) Selective release of serotonin by endogenous alkaloids, 1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinolines, (R) and (S)salsolinol, in the rat striatum; in vivo microdialysis study. Neurosci Lett 149: 115–118
Nagatsu T, Kato T, Nagatsu I, Kondo Y, Inagaki S, Iizuka R, Narabayashi H (1979) Catecholamine related enzymes in the brain of patients with Parkinsonism and Wilson's disease. Adv Neurol 24: 283–292
Nagatsu T, Wakui Y, Kato T, Fujita K, Kondo T, Yokochi F, Narabayashi H (1982) Dopamine beta-hydroxylase activity in cerebrospinal fluid of Parkinsonian patients. Biomed Res 3: 95–98
Naoi M, Nagatsu T (1986) Inhibition of monoamine oxidase by 3,4-dihydroxyphenylserine. J Neurochem 47: 604–607
Naoi M, Takahashi T, Kuno N, Nagatsu T (1987) L-Threo-3,4-dihydroxyphenylserine (DOPS) aldolase: a new enzyme cleaving DOPS into protocatechualdehyde and glycine. Biochem Biophys Res Commun 143: 482–488
Narabayashi H, Kondo T (1987) Results of double-blind study of L-threo-DOPS in parkinsonism. In: Fahn S, et al (eds) Recent developments in Parkinson's disease, vol II. Macmillan, New Jersey, pp 279–291
Narabayashi H, Mizuno Y (1993) Norepinephrine deficiency and its treatment with L-threo-DOPS in Parkinson's disease and related disorders. Parthenon, Lans New York
Narabayashi H, Kondo T, Hayashi A, Suzuki T, Nagatsu T (1981) L-threo-3,4-Dihydroxyphenylserine treatment for akinesia and freezing of parkinsonism. Proc Acad 57: 351–354
Nishino N, Fuji Y, Kondo M, Shuntoh H, Fujisawa H, Tanaka C (1987) Effects of L-threo-3,4-dihydroxyphenylserine on efflux of monoamine and acetylcholine in guinea pig brain. J Pharmacol Exp Ther 242: 621–628
Paxinos G, Watson C (1986) The rat brain in stereotaxic coordinates, 2nd ed. Academic Press, San Diego
Reches A, Jackson-Lewis V, Fahn S (1985) DL-threo-DOPS as a precursor of noradrenaline. Naunyn-Schmiedebergs Arch Pharmacol 331: 202–208
Riederer P, Birkmayer W, Seemann D, Wuketich S (1977) Brain noradrenaline and 3-methoxy-4-hydroxyphenylglycol in Parkinson's syndrome. J Neural Transm 41: 241–251
Sumi C, Ichinose H, Nagatsu T (1990) Characterization of recombinant human aromatic L-amino acid decarboxylase expressed in COS cells. J Neurochem 55: 1075–1078
Tohgi H, Abe T, Takahashi S, Takahashi J, Ueno M, Nozaki Y (1990) Effect of a synthetic norepinephrine precursor, L-threo-3,4-dihydroxyphenylserine on the total norepinephrine concentration in the cerebrospinal fluid of parkinsonian patients. Neurosci Lett 116: 194–197
Tohgi H, Abe T, Takahashi S (1993) The effects of L-threo-dihydroxyphenylserine on the total norepinephrine and dopamine concentration in the cerebrospinal fluid and freezing gait in parkinsonian patients. J Neural Transm [P-D Sect] 5: 27–34
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Maruyama, W., Nakahara, D. & Naoi, M. A new metabolic pathway of L-threo-3,4-dihydroxyphenylserine, a precursor amino acid of norepinephrine, in the brain Studies by in vivo microdialysis. J Neural Transm Gen Sect 7, 21–33 (1994). https://doi.org/10.1007/BF02252660
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DOI: https://doi.org/10.1007/BF02252660