Anxiolytic effect of fatty acids and terpenes fraction from Aloysia triphylla: Serotoninergic, GABAergic and glutamatergic implications.

Aloysia triphylla (Verbenaceae) is an aromatic medicinal plant, and it is used for the treatment of "nervous" problems as, "sadness" and "nervousness". While, there are no reports about its pharmacological activity in animal models. The objective of this work was to evaluate the anxiolytic effect of the extracts and fractions of this species and to measure the interaction of the most active fraction with serotonergic, glutamatergic and GABAergic drugs. An elevated plus maze test was carried ought where the methanol (AtM), dicloromethane (AtD) and hexanic (AtH) extracts presented anxiolytic activity in mice when exposed to the test. Also, different fractions obtained from the AtD were evaluated (AtF1, AtF2 and AtF3, 15mg/kg), and showed that fraction AtF1 possessed the anxiolytic activity, in the same model. Then, AtF1 was co-administered with different drugs, which act on GABAergic (bicuculline, picrotoxin, pentylenetetrazol, baclofen and phaclofen), or serotononinergic (DOI, 8-OH-DPAT, WAY 100635 and ketanserine) or glutamatergic (NMDA, MPEP and MK-801) systems. The anxiolytic activity of AtF1 was modified by GABAergic and serotoninergic drugs. Chemical analysis of this fraction by using GC-MS, showed that it contains hexadecanoic acid, hexadecanoic acid methyl ester, octadecanoic acid methyl ester, eicosanoic acid methyl ester, vitamin E, α-amiryn, campesterol, sitosterol, stigmastan-2,22, dien-3-ol (4) and stigmasta 5, 24 (28) dien-3-ol.

Serotonergic mechanisms are involved in antidepressant-like effects of bisbenzylisoquinolines liensinine and its analogs isolated from the embryo of Nelumbo nucifera†Gaertner seeds in mice.

OBJECTIVES: We attempted to ascertain if bisbenzylisoquinoline alkaloids, liensinine and isoliensinine from Nelumbo nucifera Gaertner have antidepressant-like effects and compare the effects with those previously obtained by their analogue neferine. METHODS: Using mice, the forced swimming test (FST) was carried out after treatment with liensinine, isoliensinine and neferine. KEY FINDINGS: Liensinine and isoliensinine elicited antidepressant-like effects in mice after the FST. Anti-immobility effects of liensinine and isoliensinine were antagonized by the 5-hydroxytryptamine1 A (5-HT1 A ) receptor antagonist WAY 100635, but not by the α1 -adrenoceptor antagonist prazosin. The anti-immobility effects of liensinine, isoliensinine and neferine were blocked by pretreatment with p-chlorophenylalanine (PCPA), which depletes serotonin (5-HT). CONCLUSIONS: These data suggest that liensinine and isoliensinine from Nelumbo nucifera Gaertner have antidepressant-like effects and that antidepressant-like effects of liensinine and its analogues are closely related to serotonergic mechanisms.

Gomisin N isolated from Schisandra chinensis augments pentobarbital-induced sleep behaviors through the modification of the serotonergic and GABAergic system.

The fruits of Schisandra chinensis have been used for the treatment of insomnia in oriental countries for more than thousands of years. However, the pharmacological properties and the mechanism of sedative and hypnotic effects have not yet been studied. Gomisin N is one of the major bioactive constituents from the fruits of Schisandra chinensis, and in this paper we reported a detailed study on the effects and mechanisms of Gomisin N on its sedative and hypnotic activity for the first time. These results implied that Gomisin N possessed weak sedative effects on locomotion activity in normal mice, and produced a dose-dependent(5-45 mg/kg, i.p.) increase in sleep duration in pentobarbital-treated mice, thus, itself did not induce sleep at higher dose which was used in this experiment (45 mg/kg, i.p.). It also can reverse the rodent models of insomnia induced by p-chlorophenylalanine (PCPA) and caffeine, which could exhibit a synergistic effect with 5-hydroxytryptophan (5-HTP) as well; furthermore, the hypnotic effects of Gomisin N were inhibited by flumazenil (a specific GABAA-BZD receptor antagonist). Altogether, these results indicated that Gomisin N produced beneficial sedative and hypnotic bioactivity, which might be mediated by the modification of the serotonergic and GABAergic system.

Effect of Jobelyn® on intruder- and isolation-induced aggressive behavior in mice.

BACKGROUND: Aggression is a violent behavior emitted against another organism that may lead to its harm or death and thus is of public health significance, which necessitates the search for agents with anti-aggressive property. This study investigated the effect of Jobelyn® (JB), a unique African polyherbal formulation, on intruder- and isolation-induced aggressive behaviors in mice. METHODS: Male mice that showed aggression after being housed individually with female counterparts for 3 weeks or kept in isolation for 4 weeks were treated orally (p.o.) with JB (5, 10 or 50 mg/kg), haloperidol (HP) (1 mg/kg), fluoxetine (FL) (10 mg/kg), p-chlorophenylalanine (PCPA) (20 mg/kg), mianserin (MS) (50 mg/kg) or distilled water (10 mL/kg) 60 min before being tested for aggression. Interaction studies involving oral administration of PCPA (20 mg/kg), FL (10 mg/kg) or MS (50 mg/kg) to aggressive mice that had received JB (5 or 10 mg/kg, p.o.) 30 min earlier were assessed. The effect of JB (5, 10 or 50 mg/kg, p.o.) on defensive behaviors was also evaluated. RESULTS: JB (5, 10 or 50 mg/kg) decreased aggressive behaviors without impairing the defensive mechanisms of mice. PCPA (20 mg/kg), an inhibitor of 5-hydroxytryptamine (5-HT) biosynthesis, increased aggressive responses and reduced the anti-aggressive effect of JB. FL (10 mg/kg), a 5-HT reuptake inhibitor, significantly suppressed aggression but did not alter the effect of JB on aggression. MS (50 mg/kg), a 5-HT receptor antagonist, reduced aggression and enhanced the effect of JB on aggression. CONCLUSIONS: These findings suggest that JB has anti-aggressive activity, which may be related to the enhancement of serotonergic system.

Serotonergic neurotoxic thioether metabolites of 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy"): synthesis, isolation, and characterization of diastereoisomers.

3,4-Methylenedioxymethamphetamine (MDMA, ecstasy) is a synthetic recreational drug of abuse that produces long-term toxicity associated with the degeneration of serotonergic nerve terminals. In various animal models, direct administration of MDMA into the brain fails to reproduce the serotonergic neurotoxicity, implying a requirement for the systemic metabolism and bioactivation of MDMA. Catechol-thioether metabolites of MDMA, formed via oxidation of 3,4-dihydroxymethamphetamine and 3,4-dihydroxyamphetamine (HHMA and HHA) and subsequent conjugation with glutathione (GSH), are selective serotonergic neurotoxicants when administered directly into brain. Moreover, following systemic administration of MDMA, the thioether adducts are present in rat brain dialysate. MDMA contains a stereogenic center and is consumed as a racemate. Interestingly, different pharmacological properties have been attributed to the two enantiomers, (S)-MDMA being the most active in the central nervous system and responsible for the entactogenic effects, and most likely also for the neurodegeneration. The present study focused on the synthesis and stereochemical analysis of the neurotoxic MDMA thioether metabolites, 5-(glutathion-S-yl)-HHMA, 5-(N-acetylcystein-S-yl)-HHMA, 2,5-bis-(glutathion-S-yl)-HHMA, and 2,5-bis-(N-acetylcystein-S-yl)-HHMA. Both enzymatic and electrochemical syntheses were explored, and methodologies for analytical and semipreparative diastereoisomeric separation of MDMA thioether conjugates by HPLC-CEAS and HPLC-UV, respectively, were developed. Synthesis, diastereoisomeric separation, and unequivocal identification of the thioether conjugates of MDMA provide the chemical tools necessary for appropriate toxicological and metabolic studies on MDMA metabolites contributing to its neurotoxicity.

Indole alkaloid marine natural products: an established source of cancer drug leads with considerable promise for the control of parasitic, neurological and other diseases.

The marine environment produces natural products from a variety of structural classes exhibiting activity against numerous disease targets. Historically marine natural products have largely been explored as anticancer agents. The indole alkaloids are a class of marine natural products that show unique promise in the development of new drug leads. This report reviews the literature on indole alkaloids of marine origin and also highlights our own research. Specific biological activities of indole alkaloids presented here include: cytotoxicity, antiviral, antiparasitic, anti-inflammatory, serotonin antagonism, Ca-releasing, calmodulin antagonism, and other pharmacological activities.

Resolution improvement by use of carboxymethyl-beta-cyclodextrin as chiral additive for the enantiomeric separation of basic drugs by capillary electrophoresis.

Three beta-cyclodextrin derivatives--carboxymethyl-, dimethyl- and hydroxypropyl-beta-cyclodextrin--were tested as chiral selectors for the enantioseparation of seven basic drugs in free solution capillary electrophoresis, using buffers made of 100 mM phosphoric acid adjusted to pH 3.0 with triethanolamine in fused silica capillaries thermostatted at 15 degrees C. The best results with respect to chiral resolution were obtained with carboxymethyl-beta-cyclodextrin (CMCD): the enantiomers of all compounds examined were completely resolved with this beta-cyclodextrin derivative. The influence of the CMCD concentration on the migration times, the apparent electrophoretic mobility difference and the resolution of the drug enantiomers was investigated thoroughly. Particularly impressive resolution values, up to 23.7, were obtained for several compounds in these capillary electrophoretic systems, using CMCD in the 5-15 mM concentration range.