Dopamine is a monoamine oxidase B substrate in man

Glover, Vivette; Sandler, M.; Owen, F.; Riley, G. J.

doi:10.1038/265080a0

Cited by 306 publications

(102 citation statements)

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“…Our study is not directly comparable with the above for several reasons: (a) the rat is known to have a diverse dopamine metabolism from monkey or man. Dopamine is metabolized by both forms of MAO (A and B) in the rat brain, MAO-A being the major component (Fowler and Benedetti, 1983), but it is preferentially oxidized by MAO-B in the human brain (Glover et al, 1977) and in rhesus monkeys (Koutsilieri et al, 2002a); (b) the studies concern only extracellular levels of dopamine and metabolites. Uninfected, uninfected/untreated (n ¼ 4); SIV, SIV-infected (n ¼ 7); SIV/mem, SIV-infected/memantine-treated (n ¼ 4).…”

Section: Discussionmentioning

confidence: 99%

Memantine Upregulates BDNF and Prevents Dopamine Deficits in SIV-Infected Macaques: A Novel Pharmacological Action of Memantine

Meisner

Scheller

Kneitz

et al. 2007

Neuropsychopharmacol

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N-methyl-D-aspartate (NMDA) receptor activation is involved in the pathogenetic cascades of neurodegenerative disorders including human immunodeficiency virus (HIV) dementia. Memantine, an uncompetitive NMDA receptor antagonist, which has been recently approved for the treatment of Alzheimer's disease, is being discussed as a potential adjunctive therapeutic substance for HIV dementia. We used simian immunodeficiency virus-infected rhesus macaques to assess the effects of memantine on brain dysfunction and brain pathology within 3-5 months after initial infection during early asymptomatic stage of disease. We had shown previously that within this time frame, marked changes were evident in the dopaminergic systems. Memantine was administered two weeks post infection, at peak viremia, in order to prevent early NMDA receptor activation due to immune mediators. We found that memantine prevented onset of dopamine deficits in the brains of SIV-infected macaques, without affecting early brain pathology or peripheral course of infection. Memantine specifically upregulated mRNA and protein expression of the neurotrophic factor brain-derived neurotrophic factor (BDNF), suggesting that the protective effect of memantine on dopamine function may be mechanistically remote from NMDA receptor antagonism. This novel pharmacological action of memantine may also be relevant for other neurodegenerative disorders and supports the involvement of neurotrophic factors in adult brain neuroprotection.

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Section: Discussionmentioning

confidence: 99%

Memantine Upregulates BDNF and Prevents Dopamine Deficits in SIV-Infected Macaques: A Novel Pharmacological Action of Memantine

Meisner

Scheller

Kneitz

et al. 2007

Neuropsychopharmacol

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“…It is unlikely that a MAO isoenzyme has a significantly different active site between rat and human. However, rat and human MAO have an opposite pharmacology for dopamine (Glover and Sandler, 1977), indicating their active sites may not be identical.…”

Section: Discussionmentioning

confidence: 99%

Phe²⁰⁸ and Ile¹⁹⁹ in Human Monoamine Oxidase A and B Do Not Determine Substrate and Inhibitor Specificities as in Rat

Geha

Chen

Shih

2000

Journal of Neurochemistry

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It has been reported previously that reciprocally switching Phe 208 and Ile 199 in rat monoamine oxidase (MAO) A and B, respectively, was sufficient to switch their substrate and inhibitor preferences. In this study, the same mutants were made in the human forms of MAO. When compared with MAO A, MAO A-F208I showed a sixfold decrease in the specificity constant k cat /K m for both the MAO A-and the MAO B-preferring substrates 5-hydroxytryptamine and ␤-phenylethylamine, respectively. The reciprocal point mutant MAO B-I199F had no effect on substrate affinity. To investigate if the region neighboring these two residues is responsible for conferring preferences, we have also made chimeric constructs by reciprocally switching the corresponding amino acid segments 159 -214 in 1304 -1309 (2000).Monoamine oxidase [MAO; amine:oxygen oxidoreductase (deaminating) (flavin-containing), EC 1.4.3.4] catalyzes the oxidative deamination of biogenic and xenobiotic amines and plays an important role in regulating their levels. It is a flavin-adenine dinucleotidecontaining enzyme located on the mitochondrial outer membrane (Nara et al., 1966;Greenawalt and Schnaitman, 1970;Shih et al., 1999). It exists as two isoenzymes, A and B. MAO A preferentially oxidizes serotonin [5-hydroxytryptamine (5-HT)] and is inhibited by low concentrations of clorgyline, whereas MAO B preferentially oxidizes low concentrations of ␤-phenylethylamine (PEA) and is inhibited by low concentrations of deprenyl. Common substrates include tyramine (Johnston, 1968;Knoll and Magyar, 1972) and dopamine. MAO A and B are composed of 527 and 520 amino acids, respectively, and have a 70% amino acid identity (Bach et al., 1988). They are closely linked on the X chromosome (Lan et al., 1989) and have an identical intron-exon organization, indicating that they are derived from a common ancestral gene (Grimsby et al., 1991). Knocking out the MAO A gene resulted in aggressive behavior in mice (Cases et al., 1995), whereas knocking out the MAO B gene resulted in mice resistant to the parkinsonism-inducing toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (Grimsby et al., 1997).To determine the region(s) responsible for the distinct substrate and inhibitor preferences of the two isoenzymes, we and other groups have made point mutants and chimeric MAO constructs exchanging corresponding portions of the isoenzymes (Gottowik et al., 1993(Gottowik et al., , 1995Wu et al., 1993;Tsugeno et al., 1995;Cesura et al., 1996;Chen et al., 1996). It has been shown that amino acid segments 161-375 in human MAO A and 152-366 in human MAO B contain part of the domain responsible for determining preference (Grimsby et al., 1996). It was later discovered that reciprocally switching amino acids F208 in rat MAO A and its corresponding residue in rat MAO B, I199, was sufficient to switch the substrate and inhibitor preferences of rat MAO A and B (Tsugeno and Ito, 1997). To determine if the human MAO equivalents of these two residues, which are located within the segments in our ea...

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“…In addition, it has been shown that (-)-deprenyl inhibits dopamine uptake in the rat striatum and forebrain (Harsing et al, 1979;Lai et al, 1980;Azzaro & Demarest, 1982) which might also result in enhancement of dopaminergic tone. In human striatum, where dopamine is a substrate for MAO-B (Glover et al, 1977), (-)-deprenyl might exert its therapeutic action in Parkinson's disease through these mechanisms.…”

Section: Discussionmentioning

confidence: 99%

Release of endogenous dopamine from rat isolated striatum: effect of clorgyline and (−)−deprenyl

Hársing

Vizi

1984

British J Pharmacology

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1 High performance liquid chromatography with electrochemical detection was used to measure the release and content of dopamine and dihydroxyphenylacetic acid (DOPAC) from rat isolated striatum. The effects of the monoamine oxidase (MAO) inhibitors clorgyline and (-)-deprenyl on dopamine and DOPAC release and contents, and the IC50 values of these compounds for inhibition of dopamine deamination in rat striatum were determined. 2 Dopamine release was significantly increased by elevated KCl (22 mM) in a Ca2+-dependent manner, and by ouabain (20 LM), whereas the release of DOPAC remained constant. The loss in striatal dopamine content during the incubation period (67 % of initial content) was far greater than the amount of dopamine recovered in the incubation fluid (16% of initial content), suggesting that much of the DOPAC, released during incubation originated from the conversion of dopamine to DOPAC within the striatum. 3 A concentration-dependent decrease in DOPAC efflux, both during rest and stimulation periods, was observed in the presence of clorgyline (10-8M-10-7M) and (-)-deprenyl (10 5M-10 4M). 4 Higher concentrations of clorgyline (10-7M) and (-)-deprenyl (10-4M), which inhibited dopamine deamination by 85-90%, enhanced both the resting and KCl-induced release of dopamine. 5 The total amount of dopamine plus DOPAC that was released in the presence of clorgyline or (-)-deprenyl did not differ from control values, suggesting that the increase in dopamine release elicited by MAO inhibitors might result from reduced degradation of dopamine to DOPAC. 6 The IC50 values of clorgyline (5 x 10-9M) and (-)-deprenyl (5 x 10-6M) for inhibition of dopamine deamination indicate that dopamine is a substrate for type A MAO in rat striatum. IntroductionIt is generally accepted that dopamine released from axon terminal varicosities of the nigrostriatal pathway has an important role in the regulation of striatal neurotransmission (Vizi et al., 1977;Dray, 1979;Lehmann & Langer, 1983). Yet the release of endogenous dopamine as a possible index of dopaminergic neural activity is not commonly measured because of the small amount of dopamine released from brain slice preparations. Drugs affecting the release of dopamine in the striatum have been investigated mainly by indirect methods such as measurement of [3H]-dopamine synthesis from [3H]-tyrosine (Glowinski, 1976) (Starke et al., 1978; Cubeddu & Hoffman, 1982). Studies with the [3H]-dopamine method, however, have often produced conflicting data. For example, when the effects of opioid peptides were studied, it was observed in one study that Pendorphin but not Met enkephalin, inhibited striatal dopamine release (Loh etal., 1976), whereas in other studies, 1-endorphin was reported to have no effect (Arbilla & Langer, 1978) and Met enkephalin was found to be inhibitory on dopamine release (Subramanian et al., 1977). Similarly, studies of the effects of neuroleptics on striatal dopamine release have yielded contradictory data (Farnebo & Hamberger, 1971;Seeman & Lee, 1975).I...

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Dopamine is a monoamine oxidase B substrate in man

Cited by 306 publications

References 13 publications

Memantine Upregulates BDNF and Prevents Dopamine Deficits in SIV-Infected Macaques: A Novel Pharmacological Action of Memantine

Memantine Upregulates BDNF and Prevents Dopamine Deficits in SIV-Infected Macaques: A Novel Pharmacological Action of Memantine

Phe²⁰⁸ and Ile¹⁹⁹ in Human Monoamine Oxidase A and B Do Not Determine Substrate and Inhibitor Specificities as in Rat

Release of endogenous dopamine from rat isolated striatum: effect of clorgyline and (−)−deprenyl

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Dopamine is a monoamine oxidase B substrate in man

Cited by 306 publications

References 13 publications

Memantine Upregulates BDNF and Prevents Dopamine Deficits in SIV-Infected Macaques: A Novel Pharmacological Action of Memantine

Memantine Upregulates BDNF and Prevents Dopamine Deficits in SIV-Infected Macaques: A Novel Pharmacological Action of Memantine

Phe208 and Ile199 in Human Monoamine Oxidase A and B Do Not Determine Substrate and Inhibitor Specificities as in Rat

Release of endogenous dopamine from rat isolated striatum: effect of clorgyline and (−)−deprenyl

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Phe²⁰⁸ and Ile¹⁹⁹ in Human Monoamine Oxidase A and B Do Not Determine Substrate and Inhibitor Specificities as in Rat