Effects of harmine on dopamine output and metabolism in rat striatum: role of monoamine oxidase-A inhibition

Iurlo, M.; Leone, Marica; Schilström, Björn; Linnér, Love; Nomikos, George G.; Hertel, P.; Silvestrini, Bruno; Svensson, Torgny H.

doi:10.1007/s002130100879

Cited by 45 publications

(37 citation statements)

References 23 publications

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“…The similar effect of genotype on HVA and 5-HIAA is not surprising since the concentrations of these two metabolites are highly correlated (r = 0.63, P < 0.0001). However, the genotype effects we observed on CSF HVA and, to a lesser extent, on 5-HIAA, were in a direction opposite to expectations based on in vitro studies of allele-associated enzyme expression; 12,14 although MAOA inhibitors are known to decrease monoamine metabolite levels, 1,44 in our sample it was the genotype conferring high, rather than low, MAOA activity that was associated with lower HVA levels. One obvious explanation for the correlation of low MAOA activity genotypes to high CSF HVA is that it is simply a chance finding.…”

Section: Discussioncontrasting

confidence: 99%

A functional polymorphism in the MAOA gene promoter (MAOA-LPR) predicts central dopamine function and body mass index

Ducci¹,

Newman²,

Funt³

et al. 2006

Mol Psychiatry

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Variation in brain monoaminergic activity is heritable and modulates risk of alcoholism and other addictions, as well as food intake and energy expenditure. Monoamine oxidase A deaminates the monoamine neurotransmitters serotonin, dopamine (DA), and noradrenalin. The monoamine oxidase A (MAOA) gene (Xp11.5) contains a length polymorphism in its promoter region (MAOA-LPR) that putatively affects transcriptional efficiency. Our goals were to test (1) whether MAOA-LPR contributes to interindividual variation in monoamine activity, assessed using levels of cerebrospinal fluid (CSF) monoamine metabolites; and (2) whether MAOA-LPR genotype influences alcoholism and/or body mass index (BMI). Male, unrelated criminal alcoholics (N = 278) and controls (N = 227) were collected from a homogeneous Finnish source population. CSF concentration of 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), and 3-methoxy-4-hydroxyphenylglycol (MHPG) were available from 208 participants. Single allele, hemizygous genotypes were grouped according to inferred effect of the MAOA alleles on transcriptional activity. MAOA-LPR genotypes had a significant effect on CSF HVA concentration (P = 0.01) but explained only 3% of the total variance. There was a detectable but nonsignificant genotype effect on 5-HIAA and no effects on MHPG. Specifically, the genotype conferring high MAOA activity was associated with lower HVA levels in both alcoholics and controls, a finding that persisted after accounting for the potential confounds of alcoholism, BMI, height, and smoking. MAOA-LPR genotype predicted BMI (P < 0.005), with the high-activity genotype being associated with lower BMI. MAOA-LPR genotypes were not associated with alcoholism or related psychiatric phenotypes in this data set. Our results suggest that MAOA-LPR allelic variation modulates DA turnover in the CNS, but does so in a manner contrary to our prior expectation that alleles conferring high activity would predict higher HVA levels in CSF. Our results are consistent with an emerging literature that suggests greater complexity in how variation in MAOA expression alters monoaminergic function. Finally, our work suggests that MAOA may be involved in the regulation of BMI. Independent samples are necessary to confirm this preliminary finding.

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Section: Discussioncontrasting

confidence: 99%

A functional polymorphism in the MAOA gene promoter (MAOA-LPR) predicts central dopamine function and body mass index

Ducci¹,

Newman²,

Funt³

et al. 2006

Mol Psychiatry

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“…Interestingly, harmine was once used as an anti-parkinsonian agent and was soon abandoned for its disappointing effectiveness [6]. Harmine and harmaline showed special affinity to the central nervous system (CNS) and exhibited extensive bioactivities such as multi-enzymes inhibitions including monoamine oxidaze type-A [7,8], cyclin-dependent kinases [9], N-acetyltransferase [10] and Na-K ATPase [11], cytotoxicity and antitumour activities [12,13], anti-bacterial activity [14], antiplasmodial activity [15], antileishmanial activity [16], immunomodulator properties [17], temperature-lowering effect [18], cardiovascular actions [19] and so on. Recent research reported that the alkaloids showed potential inhibitory effects on the acetylcholinesterase (AChE) activity using an in vitro thin-layer chromatography (TLC)-bioautographic assay, and ten alkaloids isolated were evaluated based on their inhibitory ability [20].…”

Section: Introductionmentioning

confidence: 99%

Characterization and determination of trace alkaloids in seeds extracts fromPeganum harmalalinn. Using LC-ESI-MS and HPLC

Liu

Zhao

Cheng

et al. 2013

Acta Chromatographica

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Summary. Harmaline and harmine accounted for more than 70% in composition in extracts of P. harmala. More attention, however, should be paid to the other alkaloids which would be favorable or unfavorable to the efficacy and safety of the products. It was necessary to determine these trace alkaloids in the extracts; thereafter, most of them have been characterized. Diglycoside vasicine, vasicine, vasicinone, harmalol, harmol, tetrahydroharmine, 8-hydroxy-harmine, ruine, harmaline, and harmine were separated and identified with reference substances and characteristic MS spectra in extracts by liquid chromatography-electrospray ionization-mass spectrometry (LC-ESI-MS) and high-performance liquid chromatography (HPLC). Three trace alkaloids, vasicine, harmalol, and harmol were determined using the developed chromatographic separation method subsequently. The average contents of vasicine, harmalol, and harmol in extracts of ten batches were 2.53 ± 0.73, 0.54 ± 0.19, and 0.077 ± 0.03%, respectively. The total content of the three alkaloids was 3.23 ± 0.90% (from 1.81 to 4.48%). For rough estimation of all the relative alkaloids except of harmaline and harmine, the average total areas of all peaks in extracts varied from 4.35 to 26.64% detected at 220, 254, 265, 280, and 380 nm, respectively. The results indicated that area normalization method was powerless for the quality evaluation for traditional herb medicine consisting of numerous compounds with highly differential features. It might be concluded that LC-MS or HPLC could be utilized as a qualitative and quantitative analytical method for quality control of the extracts from seeds of P. harmala L.

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“…␤-Carbolines modulate the levels of amine neurotransmitters and their metabolites in the central nervous system (Iurlo et al, 2001), inducing behavioral changes. MAO inhibition also leads these ␤-carboline alkaloids to induce hypothermic effects, probably through a serotonergic mechanism (Abdel-Fattah et al, 1995).…”

mentioning

confidence: 99%

Contribution of Individual Cytochrome P450 Isozymes to theO-Demethylation of the Psychotropic β-Carboline Alkaloids Harmaline and Harmine

Idle²,

Krausz

et al. 2003

J Pharmacol Exp Ther

113

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The psychotropic ␤-carboline alkaloids, showing high affinity for 5-hydroxytryptamine, dopamine, benzodiazepine, and imidazoline receptors and the stimulation of locus coeruleus neurons, are formed endogenously from tryptophan-derived indolealkylamines through the Pictet-Spengler condensation with aldehydes in both plants and mammals. Cytochromes P450 1A1 (18.5), 1A2 (20), and 2D6 (100) catalyzed the O-demethylation of harmaline, and CYP1A1 (98.5), CYP1A2 (35), CYP2C9 (16), CYP2C19 (30), and CYP2D6 (115) catalyzed that of harmine (relative activities). The dehydrogenation/aromatization of harmaline to harmine was not carried out by aromatase (CYP19), CYP1A2, CYP2C9, CYP2D6, CYP3A4, pooled recombinant cytochromes P450, or human liver microsomes (HLMs). Kinetic parameters were calculated for the O-demethylations mediated by each isozyme and by pooled HLMs. K cat (min Ϫ1 ) and K m (M) values for harmaline were: CYP1A1, 10. 8 and 11.8; CYP1A2, 12.3 and 13.3; CYP2C9, 5.3 and 175; CYP2C19, 10.3 and 160; and CYP2D6, 39.9 and 1.4. Values for harmine were: CYP1A1, 45.2 and 52.2; CYP1A2, 9.2 and 14.7; CYP2C9, 11.9 and 117; CYP2C19, 21.4 and 121; and CYP2D6, 29.7 and 7.4. Inhibition studies using monoclonal antibodies confirmed that CYP1A2 and CYP2D6 were the major isozymes contributing to both harmaline (20% and 50%, respectively) and harmine (20% and 30%) O-demethylations in pooled HLMs. The turnover numbers for CYP2D6 are among the highest ever reported for a CYP2D6 substrate. Finally, CYP2D6-transgenic mice were found to have increased harmaline and harmine O-demethylase activities as compared with wild-type mice. These findings suggest a role for polymorphic CYP2D6 in the pharmacology and toxicology of harmine and harmaline.The ␤-carboline alkaloids are present in plants and have been of interest due to their psychotropic properties (Picada et al., 1997). They may be formed endogenously from tryptophan-derived indolealkylamines through the Pictet-Spengler condensation with simple aldehydes or with pyruvic acid in mammals, including humans (Airaksinen and Kari, 1981;Melchior and Collins, 1982). Moreover, certain ␤-carbolines, such as pinoline, tryptoline, 6-hydroxy-tetrahydro-␤-carboline, harman, and norharman (Table 1), have been reported as normal constituents of human tissues and body fluids. Their levels in humans are usually elevated after drinking alcohol. The association of ␤-carbolines with alcohol dependence and brain damage has been suggested (Melchior and Collins, 1982;Collins, 2002).Endogenous and exogenous ␤-carboline alkaloids were reported to exert a wide spectrum of psychopharmacological and behavioral effects in the brain (Airaksinen and Kari, 1981). Most ␤-carbolines are strong reversible inhibitors of monoamine oxidase (MAO). Among them, harmaline and harmine (Table 1) exhibit the most potent inhibition toward purified MAO-A activity (Kim et al., 1997), and these are the principal active agents in Peganum harmala, a plant that has been used in traditional medicine for two millennia (Lamchou...

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Effects of harmine on dopamine output and metabolism in rat striatum: role of monoamine oxidase-A inhibition

Cited by 45 publications

References 23 publications

A functional polymorphism in the MAOA gene promoter (MAOA-LPR) predicts central dopamine function and body mass index

A functional polymorphism in the MAOA gene promoter (MAOA-LPR) predicts central dopamine function and body mass index

Characterization and determination of trace alkaloids in seeds extracts fromPeganum harmalalinn. Using LC-ESI-MS and HPLC

Contribution of Individual Cytochrome P450 Isozymes to theO-Demethylation of the Psychotropic β-Carboline Alkaloids Harmaline and Harmine

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