Hypothermic effect of harmala alkaloid in rats: Involvement of serotonergic mechanism

Abdel-Fattah, Abdel-Fattah Mohamed; Matsumoto, Kinzo; Gammaz, Hatim Abdel-Khalik; Watanabe, Hiroshi

doi:10.1016/0091-3057(95)00131-f

Cited by 62 publications

(22 citation statements)

References 14 publications

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“…These compounds have been shown to intercalate into DNA [1e3], to inhibit CDK [4,5], topisomerase [1,3,6] and monoamine oxidase [7e9], and to interact with benzodiazepine receptors (BZ) [10e12], 5-hydroxy serotonin receptors (5-HT) [13,14], dopamine (DA) [15] and imidazoline receptors [16,17]. In addition, individual b-carboline derivative might selectively interact with specific targets so as to lead to a variety of pharmacological actions in vitro and in vivo.…”

Section: Introductionmentioning

confidence: 99%

Design, synthesis and 3D-QSAR of β-carboline derivatives as potent antitumor agents

Cao

Guan

Shi

et al. 2010

European Journal of Medicinal Chemistry

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Section: Introductionmentioning

confidence: 99%

Design, synthesis and 3D-QSAR of β-carboline derivatives as potent antitumor agents

Cao

Guan

Shi

et al. 2010

European Journal of Medicinal Chemistry

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“…MAO inhibition also leads these ␤-carboline alkaloids to induce hypothermic effects, probably through a serotonergic mechanism (Abdel-Fattah et al, 1995). Hallucinogenic effects of harmaline and harmine are suggested as a result of their binding to 5-HT 2A and 5-HT 2C receptors, and tremorgenic properties are due to their interactions with benzodiazepine receptors (Lutes et al, 1988;Glennon et al, 2000;Husbands et al, 2001).…”

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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“…By oxidation, harmaline is converted into the psychoactive harmine, and upon reduction it yields d-1,2,3,4-tetrahydroharmine. Harmidine (C 13 H 14 N 2 O) in moderate dose can act as antinociceptive agent (Monsef et al, 2004), reversible mono amine oxidase (MAO) inhibitor (Abdel-Fattah et al, 1997) and in combination with other β-carbolines it bind to 5-HT receptors (Abdel-Fattah et al, 1995). Harmaline can induce spasmolytic effects with muscarinic, histaminic and β-adreno-receptors (Aitadafoun et al, 1996); while the vasorelaxant activity of harmane and harmaline is due to its ability to induce endothelial cells to release NO, and the vascular smooth muscles to inhibit the contractions induced by Ca2 + channels (Shi et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

Evaluation of analgesic and antiinflammatory activity of Ophiorrhiza nicobarica, an ethnomedicine from Nicobar Islands, India

Chattopadhyay¹,

Das²,

Mandal³

et al. 2007

Oriental Pharmacy and Experimental Medicine

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SUMMARYThis study reports the analgesic, anti-inflammatory and membrane-stabilizing property of alcoholic extract of Ophiorrhiza nicobarica (ON), a wild herb, used as an anti-infective ethnomedicine of Nicobarese and Shompen tribes of Great Nicobar Island, India. We for the first time investigated the analgesic and antiinflammatory potential of this herb in acute, subacute and chronic model of inflammation in Swiss albino mice and Wistar albino rats, along with sheep RBC-induced sensitivity and membrane stabilization. The acetic acid induced writhing, tail flick and tail immersion tests are used as a model for evaluating analgesic activity; while the carrageenin-induced paw oedema was used as the model for acute inflammation, dextran-induced oedema as sub-acute and cotton-pellateinduced granuloma as chronic inflammatory model. The probable mode by which ON mediate its effect on inflammatory conditions was studied on sheep RBC-induced sensitivity and membrane stabilization. The in vitro results revealed that the ON extract possesses significant (P < 0.05) dose dependent analgesic and antiinflammatory activity at 200 and 300 mg/kg and its fractions at 50 mg/ kg, p.o. respectively, compared to the control groups. However, the extract failed to exhibit membrane-stabilizing property as it unable to reduce the level of haemolysis of RBC exposed to hypotonic solution. The acute toxicity studies of ON extract in rats and mice revealed that the extract was nontoxic even up to 3.0 g/kg body weight of the animals, with a high safety profile. We have isolated ursolic acid, β-sitosterol and harmaline respectively, from the bioactive part of the extract. The results indicated that the O. nicobarica is indeed beneficial in primary health care, and suggest that its anti-inflammatory activity may not be related to membrane-stabilization.

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Hypothermic effect of harmala alkaloid in rats: Involvement of serotonergic mechanism

Cited by 62 publications

References 14 publications

Design, synthesis and 3D-QSAR of β-carboline derivatives as potent antitumor agents

Design, synthesis and 3D-QSAR of β-carboline derivatives as potent antitumor agents

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

Evaluation of analgesic and antiinflammatory activity of Ophiorrhiza nicobarica, an ethnomedicine from Nicobar Islands, India

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