Antidepressant potential of novel flavonoids derivatives from sweet violet (Viola odorata L): Pharmacological, biochemical and computational evidences for possible involvement of serotonergic mechanism.

Plant-derived natural constituents are of great interest in modern drug discovery due to their natural diversity. Viola odorata L has been traditionally used for the treatment of neuropsychiatric disorders. The present study was undertaken to isolate phytoconstituents including three flavonoids 5,7-Dihydroxy-3,6-dimethoxyflavone[1] 5,7,4'-trihydroxy-3',5'dimethoxyflavone [2] and 5,7,4'-trihydroxy-3'-methoxyflavone [3] from the whole plant of Viola odorata L and to investigate the antidepressant-like effects of these compounds and their possible mechanism of action using antagonists of the serotonergic, dopaminergic and adrenergic system. Classical animal models of depression including tail suspension test (TST) and forced swimming test (FST) using mice were used to evaluate the antidepressant-like effects. Mice were divided into various groups and were administered with either vehicle control, fluoxetine (FLX), or test compounds 1-3 intraperitoneally (i.p.). For experiments involving mechanism determination, mice were pretreated with 5-HT, dopamine and adrenergic antagonists. The brain 5-HT levels were determined following FST. Molecular docking studies were carried out to determine the binding affinity of compounds 1-3 to serotonergic receptors. The results indicated that compounds 1-3 at the dose of 1-30 mg/kg, i.p significantly decreased the immobility time in the FST and TST in mice. The reduction in immobility time was reversed by pre-treating the mice with pCPA (5-HT synthesis inhibitor) 100 mg/kg, i.p. and 5-HT receptor antagonists including WAY100635 (5-HT1a antagonist), ketanserin (a 5-HT2a antagonist) and ondansetron (5-HT3 antagonist) but not with prazosin (α1-adrenergic antagonist) and SCH23390 (D1 dopaminergic antagonist) or haloperidol (D2 dopaminergic antagonist). Moreover, in neurochemical assays, compounds 1-3 caused a significant increase in the 5-HT level in the brain tissue as compared to vehicle. These increases were reversed in the mice groups pretreated with pCPA. Furthermore, molecular docking results also depict that compounds 1-3 can interact with 5HT1A, 5HT2A, and 5HT3 receptors, and are more specific to the 5HT3 receptor subtype. In conclusion, the findings of this study clearly suggest that compounds 1-3 possess antidepressant-like effects which might be mediated via the serotonergic system.

Polyprenylated acylphloroglucinols from Hypericum scabrum.

Fourteen phloroglucinols, named hyperciumoxide A-N, and a known compound were isolated from air-dried aerial parts of Hypericum scabrum. The structures of these compounds were deduced on the basis of extensive 1D- and 2D-NMR experiments. Hepatoprotective properties against D-galactosamine-induced HL-7702 cell damage of isolated compounds were evaluated. Meanwhile, these compounds were also tested for antidepressant activity by inhibiting reuptake of tritiated serotonin ([3H]-5-HT) and Noradrenalinet ([3H]-NE) in rat brain synaptosomes.

Anticholinergic, antihistaminic, and antiserotonergic activity of n-hexane extract of Zanthoxylum alatum seeds on isolated tissue preparations: An ex vivo study.

OBJECTIVES: The aim of this study was to evaluate anticholinergic, antihistaminic, and antiserotonergic activity of the n-hexane extract of the seeds of Zanthoxylum alatum (ZAHE) on isolated ileum of rat and guinea pig and fundus of rat. MATERIALS AND METHODS: ZAHE was prepared using soxhlet extraction and cumulative concentration response curves were constructed using various doses on the tissues for acetylcholine (ACh), 5-hydroxytryptamine (5-HT), and histamine with or without n-hexane extract. Atropine, ketanserin, and pheniramine maleate were used as antagonists for ACh, serotonin, and histamine, respectively. RESULTS: ZAHE-induced concentration-dependent inhibition of isolated ileum and fundus in rat and ileum of guinea pig. The half maximal effective concentration (EC50) of ACh in the presence of atropine (10-6 M; P < 0.05) and ZAHE (1000 µg/ml; P < 0.01) was significantly higher than EC50of ACh alone. The EC50of 5-HT in the presence of ketanserin (10-5 M; P < 0.01) and ZAHE (1000 µg/ml; P < 0.05) was higher than EC50of 5-HT alone. Similarly, the EC50of histamine in the presence of pheniramine maleate (10-6 M; P < 0.01) and ZAHE (300 µg/ml; P < 0.01 and 1000 µg/ml; P < 0.05) was also significantly higher than EC50of histamine alone. CONCLUSION: From the study, it was observed that ZAHE shows significant anticholinergic, antiserotonergic, and antihistaminic activity. The study provides sufficient evidence that the seeds can be used in gastric disorders, cough, chest infection, etc., as per folklore claims.

Zerumbone alleviates chronic constriction injury-induced allodynia and hyperalgesia through serotonin 5-HT receptors.

Zerumbone, a bioactive sesquiterpene isolated from Zingiber zerumbet (Smith), has shown to exert antiallodynic and antihyperalgesic effects in neuropathic pain mice model in our recent study. The mechanism through which zerumbone alleviates neuropathic pain has yet to be elucidated. Thus, this study aimed to determine whether the serotonergic system, part of the descending pain modulation pathway, contributes to the antineuropathic effect of zerumbone. Participation of the serotonergic system in zerumbone-induced antiallodynia and antihyperalgesia was assessed using Dynamic Plantar Aesthesiometer von Frey test and Hargreaves plantar test respectively in chronic-constriction injury mice model. Administration of ρ-chlorophenylalanine (PCPA, 100mg/kg, i.p.) for four consecutive days to deplete serotonin (5-HT) prior to zerumbone administration blocked the antiallodynic and antihyperalgesic effects of zerumbone. Further investigation with 5-HT receptor antagonists methiothepin (5-HT1/6/7 receptor antagonist, 0.1mg/kg), WAY-100635 (5-HT1A receptor antagonist, 1mg/kg), isamoltane (5-HT1B receptor antagonist, 2.5mg/kg), ketanserin (5-HT2A receptor antagonist, 0.3mg/kg) and ondansetron (5-HT3 receptor antagonist, 0.5mg/kg) managed to significantly attenuate antiallodynic and antihyperalgesic effects of zerumbone (10mg/kg). These findings demonstrate that zerumbone alleviates mechanical allodynia and thermal hyperalgesia through the descending serotonergic system via 5-HT receptors 1A, 1B, 2A, 3, 6 and 7 in chronic constriction injury neuropathic pain mice.

Strictosidinic acid, isolated from Psychotria myriantha Mull. Arg. (Rubiaceae), decreases serotonin levels in rat hippocampus.

Psychotria is a complex genus whose neotropical species are known by the presence of glucosidic monoterpene indole alkaloids. These compounds are able to display a large range of effects on the central nervous system, such as anxiolytic, antidepressant, analgesic, and impairment of learning and memory acquisition. The aims of this study were to investigate the effects displayed by strictosidinic acid, isolated from Psychotria myriantha Mull. Arg. (Rubiaceae) leaves, on monoamine levels in rat hippocampus and on monoamine oxidase activity. A significance (p<0.01) of 83.5% reduction in 5-HT levels was observed after intra-hippocampal injection (20 µg/µl). After treatment by intraperitoneal route (10 mg/kg), a 63.4% reduction in 5-HT levels and a 67.4% reduction in DOPAC values were observed. The results indicate that strictosidinic acid seems to act on 5-HT system in rat hippocampus, possibly inhibiting precursor enzymes of 5-HT biosynthesis. The decrease verified in DOPAC levels suggests a role of strictosidinic acid in the dopaminergic transmission, probably due to an inhibition of monoamine oxidase activity, confirmed by the enzymatic assay, which demonstrated an inhibitory effect on MAO A in rat brain mitochondria.

Effect of xanthone from Kielmeyera coriacea stems on serotonergic neurons of the median raphe nucleus.

Kielmeyera coriacea Mart. (Clusiaceae), known as "Pau Santo", is used to treat several tropical diseases. The hydroethanolic extract (HE) of Kielmeyera coriacea stems and its semi-pure dichloromethane constituent (DCM) produced an anti-immobility effect in rats submitted to the forced swimming test (FST), suggesting a antidepressant-like profile. This study evaluated the effect of intra-median raphe nucleus (MRN) microinjection of 1,3,7-trihydroxy-2-(3-methylbut-2-enyl)-xanthone, present in large quantity in the HE from Kielmeyera coriacea stems, on immobility behaviour in the FST in rats. The effects of xanthone were compared with intra-MRN microinjections of Way100635 (5-HT1A antagonist) or (+) 8-OH-DPAT (5-HT1A agonist). Locomotor activity in the open-field test (OFT) was evaluated as a complementary measure. Xanthone (0.3ng) or Way100635 (2.5microg) reduced, whereas (+) 8-OH-DPAT (5.0microg) increased immobility time in the FST. Way100635 (2.5 or 5.0microg) completely reversed the effects of (+) 8-OHDPAT (5.0microg), and potentiated the anti-immobility effect of the ineffective dose of xanthone (0.2ng) in the FST. The association of effective doses of (+) 8-OH-DPAT (5.0microg) and xanthone (0.3ng) annulled the effect of each compound on immobility time. These results suggest that xanthone acts as an antagonist at 5-HT1A autoreceptors in MRN and increases serotonin (5-HT) availability in projection regions, proving to be a prototype drug that may be useful in mood isorders such as depression, or indeed be a beneficial adjunctive treatment improving the efficacy and/or accelerating the effects of antidepressant drugs in patients with major depression.

Inhibition of [3H]-LSD binding to 5-HT7 receptors by flavonoids from Scutellaria lateriflora.

The hot water and 70% ethanol extracts of dried mad-dog skullcap (Scutellaria lateriflora) both bound to the 5-HT(7) receptor, with 87.2 +/- 6.2% and 56.7 +/- 1.3% inhibition of [(3)H]-LSD binding to the receptor at 100 microg/mL, respectively. The on-line analysis of a 70% ethanol extract by HPLC-UV/MS resulted in the identification of five flavones (1-5). Fractionation of the ethanol extract resulted in the isolation of three flavone-glucuronides (6-8) and a flavanone-glucuronide (9), including one new compound, lateriflorin (5,6,-dihydroxy-7-glucuronyloxy-2'-methoxyflavone) (8). The structure of 8 was determined by NMR ((1)H NMR, (13)C NMR, and NOESY experiments) and MS analysis. From the results obtained in the testing of the pure compounds, it is evident that the activity on the 5-HT(7) receptor is at least partly due to the presence of flavonoids. Scutellarin and ikonnikoside I showed the highest inhibition of [(3)H]-LSD binding with IC(50) values of 63.4 and 135.1 microM, respectively.

Inactivation of a serotonin-gated ion channel by a polypeptide toxin from marine snails.

The venom of predatory marine snails is a rich source of natural products that act on specific receptors and ion channels within the mammalian nervous system. A 41-amino acid peptide, final sigma-conotoxin GVIIIA, was purified on the basis of its ability to inactivate the 5-HT3 receptor, an excitatory serotonin-gated ion channel. final sigma-Conotoxin contains a brominated tryptophan residue, which may be important for peptide activity because the endogenous ligand for the 5-HT3 receptor is a hydroxylated derivative of tryptophan. final sigma-Conotoxin inactivates the 5-HT3 receptor through competitive antagonism and is a highly selective inhibitor of this receptor. Serotonin receptors can now be included among the molecular targets of natural polypeptide neurotoxins.

Histaminergic and serotonergic receptor blocking substances from the medicinal plant Garcinia mangostana.

A crude methanolic extract of the fruit hull of Mangosteen, Garcinia mangostana L. inhibited the contractions of isolated thoracic rabbit aorta induced by histamine and serotonin. The extract of the fruit hull has been fractionated by silica gel chromatography, monitoring the pharmacological activity to give alpha- and gamma-mangostin. On the basis of pharmacological data, it is suggested that alpha-mangostin and gamma-mangostin are a histaminergic and a serotonergic receptor blocking agent, respectively.

Bioactive constituents of Chinese natural medicines. I. New sesquiterpene ketones with vasorelaxant effect from Chinese moxa, the processed leaves of Artemisia argyi Levl. et Vant.: moxartenone and moxartenolide.

Two new sesquiterpene ketones, moxartenone and moxartenolide, and three octadecadienoic acids were isolated from Chinese moxa, the processed leaves of Artemisia argyi LEVL. et VANT., together with two sesquiterpenes, five triterpenes, two phenyl propanoids and three polyoxyflavones. The chemical structures of new sesquiterpenes, moxartenone, moxartenolide, and octadecadienoic acids were determined on the basis of chemical and physiochemical evidence. Moxartenolide was found to inhibit the contractions induced by a high concentration of K+, by norepinephrine, and by serotonin in isolated aortic strips of rat, while moxartenone showed little activity.

New steroid acids from Antrodia cinnamomea, a fungal parasite of Cinnamomum micranthum.

Three new steroids, zhankuic acids A [1], B [2], and C [3], were isolated from the fruiting bodies of Antrodia cinnamomea by bioassay-guided fractionation. The structures of these compounds were elucidated by chemical reactions and detailed analysis of their 1H- and 13C-nmr spectra. Biological studies revealed that 1 exhibited cytotoxic activity against P-388 murine leukemia cells and 2 showed weak anticholinergic and antiserotonergic activities.

Serotonergic receptor antagonist from Nandina domestica Thunberg.

A crude methanolic extract of the fruit of Nandina domestica Thunberg strongly inhibits serotonin-induced contractions of the rabbit aorta. The extract of the fruit has been fractionated to afford nantenine (O- methyldomesticine ) as the active agent.