d-DOPA and l-DOPA similarly elevate brain dopamine and produce turning behavior in rats

Karoum, Farouk; Freed, William J.; Chuang, Lin-Whei; Cannon-Spoor, Eleanor; Wyatt, Richard Jed; Costa, E.

doi:10.1016/0006-8993(88)91176-6

Cited by 22 publications

(15 citation statements)

References 9 publications

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“…In unilaterally 6‐hydroxydopamine (6‐OHDA)‐lesioned rats, d ‐dopa (i.p.) was shown to have similar efficacy as l ‐dopa in inducing circling, but the onset of turning was delayed compared with that induced by l ‐dopa 2,3 . The delayed onset in action was also observed by Brannan et al ., who administered d ‐dopa intragastrically to unilaterally 6‐OHDA‐lesioned rats; in addition, the potency of d ‐dopa was found to be 40% of that of l ‐dopa 4 .…”

Section: Introductionsupporting

confidence: 63%

d‐DOPA IS UNIDIRECTIONALLY CONVERTED TO l‐DOPA BY d‐AMINO ACID OXIDASE, FOLLOWED BY DOPA TRANSAMINASE

Zhou

Konno

et al. 2006

Clin Exp Pharma Physio

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1. Many studies have shown that administration of d-3, 4-dihydroxyphenylalanine (D-dopa) produces contralateral rotation in hemi-parkinsonian animals comparable to L-dopa, with less potency and slower onset. It was postulated that D-dopa was converted to L-dopa to produce these effects. 2. To investigate the postulated chiral inversion of D-dopa to L-dopa and the related mechanism, an enantiomeric separation method for D- and L-dopa using HPLC was first established. Then, rat kidney homogenates containing D-dopa or L-dopa were incubated and subjected to HPLC to detect traces of respective enantiomer generation. The mechanism of the chiral inversion of d-dopa was explored by direct measurement of the production of L-dopa in kidney homogenates. D-dopa incubations containing different concentrations of an inhibitor of D-amino acid oxidase (DAAO) and an inhibitor of dopa transaminase were measured for L-dopa generation using HPLC. The role of DAAO in the chiral inversion of D-dopa to L-dopa was further investigated by using purified DAAO and mutant ddY/DAAO- mouse kidney lacking DAAO activity. 3. In rat kidney homogenate, D-dopa was, indeed, converted to L-dopa, whereas L-dopa was not converted to D-dopa. Sodium benzoate, a selective inhibitor of DAAO, blocked L-dopa generation in a concentration-dependant manner. In contrast with kidney homogenates of wild-type ddY/DAAO+ mice, those of mutant ddY/DAAO- mice lacking DAAO activity did not convert D-dopa to L-dopa unless exogenous DAAO protein was added. Conversely, when carbidopa, an inhibitor of dopa transaminase, was added to the homogenates, significant inhibition of L-dopa production was noted. 4. These results prove the proposal that d-dopa undergoes unidirectional chiral inversion and further suggest that D-dopa is first oxidatively deaminated by DAAO to its alpha-keto acid and then transaminated by dopa transaminase to L-dopa.

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Section: Introductionsupporting

confidence: 63%

d‐DOPA IS UNIDIRECTIONALLY CONVERTED TO l‐DOPA BY d‐AMINO ACID OXIDASE, FOLLOWED BY DOPA TRANSAMINASE

Zhou

Konno

et al. 2006

Clin Exp Pharma Physio

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“…2g, increasing the dose of l ‐DOPA (100 mg/kg) results in a higher increase in DA levels in KO than in wild‐type mice. This higher DA oxidative metabolism in wild‐type mice suggests that MAO B oxidizes DA and that l ‐DOPA may be partially taken up by astrocytes, which contain high levels of MAO B (Karoum et al, 1988). In line with this, when wild‐type mice were pretreated with l ‐deprenyl, the l ‐DOPA‐induced difference in the increase in levels of DA and metabolites between wild‐type and KO mice was abolished.…”

Section: Discussionmentioning

confidence: 99%

Striatal Dopamine Metabolism in Monoamine Oxidase B‐Deficient Mice : A Brain Dialysis Study

Fornai

Chen

Giorgi

et al. 1999

Journal of Neurochemistry

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Abstract:We have studied striatal dopamine (DA) metabolism in monoamine oxidase (MAO) B-deficient mice using brain microdialysis. Baseline DA levels were similar in wild-type and knock-out (KO) mice. Administration of a selective MAO A inhibitor, clorgyline (2 mg/kg), increased DA levels and decreased levels of its metabolites in all mice, but a selective MAO B inhibitor, l-deprenyl (1 mg/ kg), had no effect. Administration of 10 and 50 mg/kg L-DOPA, the precursor of DA, increased the levels of DA similarly in wild-type and KO mice. The highest dose of L-DOPA (100 mg/kg) produced a larger increase in DA in KO than wild-type mice. This difference was abolished by pretreating wild-type mice with l-deprenyl. These results suggest that in mice, DA is only metabolized by MAO A under basal conditions and by both MAO A and B at high concentrations. This is in contrast to the rat, where DA is always metabolized by MAO A regardless of concentration. Key Words: Brain dialysis-L-DOPA-DopamineMonoamine oxidase B knock-out mice-Monoamine oxidase. J. Neurochem. 73, 2434Neurochem. 73, -2440Neurochem. 73, (1999.It is important to study dopamine (DA) metabolism because it underlies the molecular basis of Parkinson's disease (PD) and the action of many psychotropic drugs. DA is metabolized by monoamine oxidase (MAO; amine: oxygen oxidoreductase, flavin-containing; EC 1.4.3.4) to L-3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA). MAO exists in two isoenzymes, A and B, with different substrate and inhibitor specificities (Knoll and Magyar, 1972;Shih et al., 1999). These two isoenzymes are encoded by two different genes with 70% sequence identity (Bach et al., 1988). They are both located on the X chromosome (Lan et al., 1989) and have identical intron-exon organization, suggesting that they are derived from the same ancestral gene (Grimsby et al., 1991). MAO A preferentially metabolizes serotonin (5-HT), whereas MAO B has a higher affinity for phenylethylamine (PEA). MAO A and B have similar affinity for DA.Most studies on the role of MAO A and B in DA metabolism have been carried out in rats despite the fact that rats have different sensitivity to DA neurotoxins than mice and primates (for review, see Fornai et al., 1997b). These studies suggest that under basal conditions (Kato et al., 1986;Butcher et al., 1990) and in the presence of high substrate concentrations (Wachtel and Abercrombie, 1994;Finberg et al., 1995), DA is metabolized only by MAO A in the rat. However, the few studies that have been carried out using other animal species have shown different results. For instance, in humans DA is also metabolized by MAO B (Glover et al., 1977). In the guinea pig, DA is metabolized by both MAO A and B (Juorio et al., 1994). Similarly, L-DOPA is metabolized by both MAO A and B in primate striatal homogenates (Di Monte et al., 1996). Increased extracellular DA levels are reported following systemic administration of L-DOPA and selective inhibition of MAO B in monkeys (Finberg et al., 1998). Because several stu...

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“…When D‐DOPA (Fig. 4A), the stereoisomer of L‐DOPA, is administered, it is converted to dihydroxyphenylpyruvic acid by DAO, which is followed by transamination from α‐keto acid to L‐DOPA via what is known as the alternative pathway for dopamine biosynthesis (summarized in Scheme ) 12,13. Indeed, the slower utilization of D‐DOPA, as well as the longer retention of its metabolites in the brain,31 makes the combination of the two isomers a more efficacious treatment for Parkinson's disease than does L‐DOPA alone 32…”

Section: Oxidation Of D‐dopa By Hdao: Alternative Pathway For Dopaminmentioning

confidence: 99%

“… General and alternative dopamine synthetic pathways. When administered, D‐DOPA is converted to DHPPA by D‐amino acid oxidase, after which the α‐keto acid is transaminated to L‐DOPA 12,13. Hypothetical reactions are indicated by dashed lines.…”

Section: Oxidation Of D‐dopa By Hdao: Alternative Pathway For Dopaminmentioning

confidence: 99%

“…In this context, it is also noteworthy that 3,4‐dihydroxy‐ D ‐phenylalanine (D‐DOPA), the stereoisomer of 3,4‐dihydroxy‐ L ‐phenylalanine (L‐DOPA), which is commonly used in the treatment of Parkinson's disease, is reportedly metabolized by DAO. In fact, when D‐DOPA is administered, it is converted to dopamine via an alternative biosynthetic pathway 12,13. Thus, the potential clinical importance of D‐amino acid oxidase in humans (hDAO) highlights the need for structural and functional analyses of this enzyme because inhibitors acting selectively on hDAO are being intensively sought for clinical purposes 14…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Human D‐amino acid oxidase: an update and review

Kawazoe

Park

Iwana

et al. 2007

The Chemical Record

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The flavoprotein D-amino acid oxidase (DAO) degrades the gliotransmitter D-Ser, a potent activator of N-methyl-D-aspartate-type glutamate receptors. A body of evidence suggests that DAO, together with its activator, G72 protein, may play a key role in the pathophysiology of schizophrenia. It has also been suggested that 3,4-dihydroxy-D-phenylalanine (D-DOPA), the stereoisomer of 3,4-dihydroxy-L-phenylalanine (L-DOPA), is oxidized by DAO and converted to dopamine via an alternative biosynthetic pathway. We determined the crystal structures of human DAO in complex with the reaction products of two clinically important substrates, D-Ser and D-DOPA. Kinetic data show that the maximum velocity is much greater for D-DOPA than that for D-Ser, which strongly supports the proposed alternative pathway for dopamine biosynthesis in the treatment of Parkinson's disease. In addition, biochemical characterization of human DAO indicates that it binds FAD more weakly than does porcine D-amino acid oxidase (pDAO) and exists as a stable homodimer, even in the apoprotein form. Determination of the structures of human DAO in various states reveals that, in contrast to pDAO, the hydrophobic-Val-Ala-Ala-Gly-Leu (VAAGL) stretch (residues 47-51, structurally ambivalent peptide) located at the si-face of the flavin ring assumes a uniquely stable conformation, which provides a structural basis for the unique kinetic features of human DAO.

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d-DOPA and l-DOPA similarly elevate brain dopamine and produce turning behavior in rats

Cited by 22 publications

References 9 publications

d‐DOPA IS UNIDIRECTIONALLY CONVERTED TO l‐DOPA BY d‐AMINO ACID OXIDASE, FOLLOWED BY DOPA TRANSAMINASE

d‐DOPA IS UNIDIRECTIONALLY CONVERTED TO l‐DOPA BY d‐AMINO ACID OXIDASE, FOLLOWED BY DOPA TRANSAMINASE

Striatal Dopamine Metabolism in Monoamine Oxidase B‐Deficient Mice : A Brain Dialysis Study

Human D‐amino acid oxidase: an update and review

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