Estrogen receptors-ß and serotonin mediate the antidepressant-like effect of an aqueous extract of pomegranate in ovariectomized rats.

Pomegranate (Punica granatum) fruit is of particular interest because of its high nutritional value and therapeutic actions. Recently, we showed that an aqueous extract of pomegranate (AE-PG) given by oral route induced antidepressant-like actions mediated by estrogen receptors (ERs) suggesting its potential to function as an alternative to estrogen therapy replacement in menopause-related depression treatment. Orally administered AE-PG allows the biotransformation of ellagitannins into active estrogenic compounds through the intestinal microbiota. However, it is necessary to know if compounds that do not need to be biotransformed by the intestinal microbiota are involved in the antidepressant-like effects. Therefore, the first aim of this study was to determine if AE-PG produces an antidepressant-like effect when administered intraperitoneally. Also, to determine the participation of specific ER-subtypes (α or ß) and to analyze the role of the serotonergic system. Young female Wistar rats were ovariectomized as a surgical model of menopause. The intraperitoneal administration of AE-PG (1 mg/kg; i. p.) was evaluated in the forced swimming test and open field tests. Also, the ERα antagonist (TPBM; 50 µg/rat; s. c.) or the ERß antagonist (PHTPP; 25 µg/rat; s. c.) were administered with AE-PG to analyze the participation of the specific ERs. Finally, the effect of the serotonin neurotoxin 5,7-DHT (200 µg/rat; i. c.v.) on the antidepressant-like effect of the AE-PG was studied in independent experimental groups. RESULTS: showed that AE-PG administered by intraperitoneal route induced antidepressant-like effects. This result suggests that gut microbiota biotransformation is not necessary to exert its actions. The mechanism of action involves the activation of the ERß and the serotonergic system. Altogether, this information contributes to the elucidation of the antidepressant action of the pomegranate fruit, which could be further considered as an alternative treatment for depression during menopause.

Anxiolytic- and anxiogenic-like effects of Montanoa tomentosa (Asteraceae): Dependence on the endocrine condition.

ETHNOPHARMACOLOGICAL RELEVANCE: Montanoa tomentosa Cerv. (MT) is a native plant from Mexico used in traditional medicine as a remedy for reproductive impairments and relaxing effects. In previous studies, it has been shown that the endocrine state could modify the antianxiety-like actions of anxiolytic compounds. Although women are the primary user of MT, no studies have evaluated the potential impact of the endocrine milieu on its anti-anxiety actions. AIMS OF THE STUDY: Ascertain the antianxiety effects of M. tomentosa in rats with different hormonal conditions, and to analyze the participation of the GABAA receptor in ovariectomized rats treated with MT. MATERIALS AND METHODS: The animal model of anxiety used was the elevated plus-maze (EPM). Rats' endocrine conditions were: a) Low hormone levels (rats in diestrus I and II phases); b) High hormone levels (proestrus/estrus phases); c) No hormones (ovariectomized rats); and d) Rats under progesterone withdrawal (PW). To evaluate the participation of the GABAA receptor in the anxiolytic-like action of MT the antagonist picrotoxin was used. RESULTS: Results showed that MT induced dose-dependent anxiolytic-like actions in rats with low hormone level conditions. Also, MT reduced anxiety-like behavior in female rats under PW, in contrast to diazepam which was ineffective. MT's anxiolytic-like effect was blocked by picrotoxin, suggesting the participation of the GABAA receptor complex. However, increased anxiety-like behavior was observed in rats with a high hormone level condition and low doses of MT. CONCLUSIONS: Beneficial anxiolytic-like actions of MT are observed under low hormone conditions, particularly in the PW challenge (a condition that can be related to a premenstrual period). Furthermore, the participation of the GABAA receptor is evidenced. However, hormonal variations could induce the opposite effects, hence women should be cautious.

Aqueous Extract of Pomegranate Alone or in Combination with Citalopram Produces Antidepressant-Like Effects in an Animal Model of Menopause: Participation of Estrogen Receptors.

It has been reported that the aqueous extract of pomegranate (AE-PG) has polyphenols with estrogenic-like activities. The present work determines if AE-PG alone or in combination with the selective serotonin reuptake inhibitor, citalopram, has antidepressant-like effects. It was also analyzed the participation of estrogen receptors (ER). AE-PG (0.1, 1.0, 10, or 100 mg/kg) was evaluated in ovariectomized female Wistar rats subjected to the forced swimming test. The effects induced by AE-PG were compared with those of citalopram (2.5, 5.0, 10, and 20.0 mg/kg) and 17ß-estradiol (E2; 2.5 5.0, and 10 µg/rat). Likewise, the combination of suboptimal doses of AE-PG (0.1 mg/kg) plus citalopram (2.5 mg/kg) was evaluated. To determine if ER participates in the antidepressant-like action of pomegranate, the estrogen antagonist tamoxifen (15 mg/kg) was administered with AE-PG (1 mg/kg). AE-PG produced antidepressant-like actions with a similar behavioral profile induced by citalopram and E2. Suboptimal doses of citalopram plus AE-PG produced antidepressant-like effects. Tamoxifen was able to block AE-PG's antidepressant-like actions. These results confirm the participation of ER in AE-PG's antidepressant-like effects. Furthermore, the additive effects observed with the combined treatment of AE-PG plus citalopram could be advantageous in the treatment of depressive disorders, such as menopause.

Mexican medicinal plants with anxiolytic or antidepressant activity: Focus on preclinical research.

ETHNOPHARMACOLOGICAL RELEVANCE: Anxiety and depression are considered the most prevalent psychiatric disorders worldwide. In Mexico, the use of medicinal plants to alleviate the symptoms associated with these psychiatric disorders is increasing. However, there is little scientific evidence that validates the efficacy of these plants. This evidence needs to be critically revised, and further studied to provided scientific support for their use. AIM OF THE STUDY: To identify the plants that are used in Mexico for the treatment of disorders related to anxiety and depression, and to review the current preclinical and when available, clinical information of these plants. METHODS: We searched in scientific databases (Pubmed, Web of Science, Scopus and other web sources such as "Biblioteca digital de la medicina tradicional Mexicana" ) for Mexican plants used for the treatment of anxiety and depression that have been analyzed in preclinical studies. Additional information was obtained from published books. For this review, we also consider those plants used in Mexican traditional medicine for the treatment of "nervios," "susto" or "espanto;" common terms that describe symptoms related to anxiety and depression disorders. RESULTS: The bibliographic search identified 49 plants used in Mexican traditional medicine for the treatment of disorders related to anxiety and depression. From all these plants, 59% were analyzed in preclinical research, and only 8% were tested in clinical studies; only a few of these studies tried to elucidate their mechanism of action. In general, it is proposed that the plant extracts interact with the GABAergic system. However, only part of these studies attempted to analyze other neurotransmitter systems. Finally, in some cases, drug-herbal interactions were reported. CONCLUSIONS: There is a large number of Mexican medicinal plants used as a treatment for anxiety and depression disorders. Although some of these plants have been studied in preclinical research, in most cases these studies are preliminary, and the understanding of the mechanism of action is inconclusive. The need for systematic studies in preclinical and clinical research is evident, and efforts should be done to fulfill these research. Finally, it is important also to study possible drug-herbal interactions to establish specific recommendations for people that use these plants as anxiolytic or antidepressant treatments either alone or in combination with another type of medicine.

Preclinical characterization of toluene as a non-classical hallucinogen drug in rats: participation of 5-HT, dopamine and glutamate systems.

RATIONALE: Toluene is a misused inhalant with hallucinogenic properties and complex effects. Toluene blocks N-methyl-D-aspartate (NMDA) receptors, releases dopamine (DA), and modifies several neurotransmitter levels; nonetheless, the mechanism by which it produces hallucinations is not well characterized. OBJECTIVES: This study aims (a) to study toluene's effects on the 5-HT2A-mediated head-twitch response (HTR), dopamine (DA), and serotonin (5-HT) tissue levels in discrete brain regions; (b) to compare the actions of toluene, ketamine, and 1-[2,5-dimethoxy-4-iodophenyl]-2-aminopropane (DOI) on HTR; and (c) to study the pharmacological blockade of toluene's and ketamine's effects by selective drugs. METHODS: Independent groups of rats inhaled toluene (500-12,000 ppm) for 30 min during which the occurrence of serotonergic signs was analyzed. Brains were obtained after exposure to determine DA and 5-HT levels by HPLC. RESULTS: Toluene concentration-dependently induced HTR. Other serotonin syndrome signs were evident at high concentrations. Toluene (4000 and 8000 ppm), and ketamine (3 and 10 mg/kg), significantly increased 5-HT levels in the frontal cortex (FC) striatum, hippocampus, and brain stem, as well as DA levels in the striatum and FC. Pretreatment with ketanserin (5HT2A/2C receptor antagonist), M100907 (selective 5-HT2A receptor antagonist), D-serine (co-agonist of the NMDA receptor glycine site), and haloperidol (D2 receptor antagonist) significantly decreased toluene's and ketamine's actions. The 5HT1A receptor antagonist WAY100635 had no effect. CONCLUSION: Toluene stimulates 5HT2A and 5HT2C receptors, and increases 5-HT and DA levels. These actions are similar to those produced by ketamine and involve activation of a complex neurotransmitter network that includes NMDA receptor antagonism.

GABAA/benzodiazepine receptor complex mediates the anxiolytic-like effect of Montanoa tomentosa.

ETHNOPHARMACOLOGICAL RELEVANCE: Montanoa tomentosa also named Cihuapatli is a native plant of Mexico that has been used in traditional medicine for the last five centuries mainly as a remedy for reproductive impairments. However, there are reports indicating that this plant was also consumed by Mexican ancient people for its relaxing properties. In order to corroborate this information, the present study was conducted to evaluate the effect of Montanoa tomentosa lyophilisate (MT) on rat׳s anxiety-like behavior and to analyze its mechanism of action. MATERIALS AND METHODS: The anxiolytic-like action of MT (1.5, 3.0, 6.0 and 12.0 mg/kg) was investigated in male Wistar rats tested in three animal models of anxiety: the burying behavior, the elevated plus maze and the hole-board tests. As a positive control, the anti-anxiety effects of different doses of the selective GABAA receptor agonist muscimol were also analyzed. In order to evaluate the participation of the GABAA and oxytocin receptors in the anxiolytic-like actions of MT, the GABAA receptors blockers picrotoxin (0.25 and 0.50 mg/kg), bicuculline (2.0 mg/kg) and flumazenil (5.00 and 10.0 mg/kg), the neurosteroid inhibitor finasteride (50.0 and 100 mg/kg) and the oxytocin receptor antagonist atosiban (0.25 µg) were used. Finally, to evaluate general activity, and motor coordination, the open field and rota-rod tests were used. RESULTS: MT at 3.0 mg/kg showed anxiolytic-like effects in the three anxiety paradigms without affecting reactivity, general motor activity or motor coordination; however, at higher doses sedative effects were observed. Picrotoxin (0.25 and 0.50 mg/kg), flumazenil (10.0 mg/kg) and finasteride (100 mg/kg) antagonized the anxiolytic-like actions of MT in the burying behavior test. In the plus maze and hole-board tests bicuculline (2.0 mg/kg) blocked the effects of the plant as well. Atosiban (0.25 µg) did not antagonize the anxiolytic-like actions of MT. CONCLUSIONS: The results corroborate the anxiolytic-like actions of Montanoa tomentosa and suggest that this effect is mediated through GABAA receptors but not oxytocin receptors.

Anxiolytic-like and sedative actions of Rollinia mucosa: possible involvement of the GABA/benzodiazepine receptor complex.

This study evaluated possible CNS effects of a hexane extract of leaves from Rollinia mucosa (Jacq.) Baill. (Annonaceae). This plant extract induced anxiolytic-like actions similar to those induced by diazepam in the avoidance exploratory behavior paradigm. Its significant activity was shown at doses from 1.62 to 6.25 mg/kg. It also enhanced pentobarbital-induced hypnosis time, and at high doses produced motor coordination impairment. The benzodiazepine (BDZ) receptor binding, evaluated by in vitro autoradiography following a single administration of R. mucosa, revealed that this plant extract reduced BDZ binding in the hippocampus (29%), amygdala (26%), and temporal cortex of mice (36%). In conclusion, the present findings support the proposal that R. mucosa may induce central nervous system (CNS) depressant effects, presumably through an interaction with the GABA/benzodiazepine receptor complex.

The biological activity of derivatives of 2-[(o-; and p-substituted)aminophenyl]-3H-5-[(o-; and p-substituted)phenyl]-7-chloro-1,4-benzodiazepines and 1-alkyl-3H-5-[(o-; and p- substituted) phenyl]-7-chloro-1,4-benzodiazepin-2-one.

Eight of a series of twelve new 2-[(o-; and p-substituted)aminophenyl]-3H-5-[(o-; and p-substituted)phenyl]-7-chloro-1,4-benzodiazepinines (VI, 1-12; Fig. 1) and two of eleven new 1-alkyl-3H-5-[(o-; and p-substituted)phenyl]-7-chloro-1,4-benzodiazepin-2-one (IV, 1-12; Fig. 2) were tested for their pharmacological and/or biological activity as anxiolytics.

Lignans from leaves of Rollinia mucosa.

A new furofuranic lignan named (+)-epimembrine together with known (+)-epieudesmine and (+)-epimagnoline were isolated from leaves of R. mucosa. Their structures were determined by spectroscopic data. Palmitone and a mixture of beta-sitosterol and stigmasterol were also isolated.