Fábio Fagundes da Rocha

Antinociceptive and anti-inflammatory kaempferol glycosides from Sedum dendroideum.

AIM OF THE STUDY To identify the compounds responsible for the antinociceptive and anti-inflammatory effects previously described for Sedum dendroideum, through bioassay-guided fractionation procedures. MATERIALS AND METHODS Antinociceptive activity was evaluated through mouse acetic acid-induced writhing model. The anti-inflammatory activity was assessed through croton oil-induced mouse ear oedema and carrageenan-induced peritonitis. RESULTS The Sedum dendroideum juice afforded seven known flavonoids identified with basis on NMR data. The oral administration of the major kaempferol glycosides kaempferitrin [1] (17.29 micromol/kg), kaempferol 3-O-beta-glucopyranoside-7-O-alpha-rhamnopyranoside [2] (16.82 micromol/kg), kaempferol 3-O-neohesperidoside-7-O-alpha-rhamnopyranoside [3] (13.50 micromol/kg) or alpha-rhamnoisorobin [5] (23.13 micromol/kg) inhibited by 47.3%, 25.7%, 60.2% and 58.0%, respectively, the acetic acid-induced nociception (indomethacin: 27.95 micromol/kg, p.o.; 68.9%). Flavonoids 1, 2, 3 or 5, at the same doses, reduced by 39.5%, 46.5%, 35.6% and 33.3%, respectively, the croton oil-induced oedema (dexamethasone: 5.09 micromol/kg, s.c.; 83.7%) and impaired leukocyte migration by 42.9%, 46.3%, 50.4% and 49.6%, respectively (dexamethasone: 5.09 micromol/kg, s.c.; 66.1%). CONCLUSIONS Our findings show that the major kaempferol glycosides may account for the renowned medicinal use of Sedum dendroideum against pain and inflammatory troubles.

Plurality of anxiety and depression alteration mechanism by oleanolic acid.

Our study sought to evaluate the anxiolytic and antidepressant activities of oleanolic acid as well as the neural mechanisms involved. Animal models such as barbiturate sleep-induction, light–dark box, elevated plus maze, forced swimming test, tail suspension test and open field test were conducted. Male Albino Swiss mice were treated orally with vehicle 10 mL/kg, fluoxetine 20 mg/kg, imipramine 15 mg/kg, diazepam 1 mg/kg or oleanolic acid 5–40 mg/kg. Pretreatment (intraperitoneal) of animals with pentylenetetrazole (PTZ) 20 mg/kg, 1-(2-methoxyphenyl)-4-[4- (2-phthalimido) butyl]piperazine hydrobromide (NAN-190) 0.5 mg/kg, p-chlorophenylalanine methyl ester (PCPA) 100 mg/kg or α-methyl-p-tyrosine (AMPT) 100 mg/kg, WAY100635 (WAY) 0.3 mg/kg, prazosin (PRAZ) 1 mg/kg, yohimbine 2 mg/kg as well as monoamine oxidase assay and hippocampal brain-derived neurotrophic factor (BDNF) quantification were carried out. Oleanolic acid potentiated the hypnotic effect of barbiturate and demonstrated an anxiolytic effect in both the light–dark box and elevated plus maze. This effect was not reversed by PTZ. Acute and/or chronic oral treatment of mice with oleanolic acid (5−20 mg/kg) elicited an antidepressant effect in the forced swimming test and the tail suspension test without interfering with the locomotor activity. The antidepressant effect of oleanolic acid was attenuated by NAN-190, AMPT, PCPA, WAY and PRAZ. Although monoamine oxidase activity remained unaltered by oleanolic acid, chronic administration of oleanolic acid augmented hippocampal BDNF level. These findings demonstrate multiple mechanisms of the anxiolytic and antidepressant effect of oleanolic acid.

Evaluation of the antinociceptive and anti-inflammatory effects of the acetone extract from Anacardium occidentale L

The stem bark of Anacardium occidentale L. (Anacardiaceae), commonly called cashew, is used in Brazilian traditional medicine for the treatment of gastric and inflammatory disorders. The present study was carried out to investigate the in vivo anti-inflammatory activities of the acetone extract (AE) of the stem bark of A. occidentale. We evaluated the pharmacological activities of this plant material through the analgesic, antiedematogenic and chemotaxic inhibitory effects produced by the AE. The oral administration (p.o.) of mice with the AE (0.1, 0.3 and 1.0 g/kg) or positive control indomethacin (10 mg/kg) inhibited acetic acid-induced writhing by 18.9, 35.9, 62.9 and 68.9%, respectively (ID50% = 530 mg/kg). The highest dose of the AE was able to inhibit croton oil-induced ear edema formation by 56.8% (indomethacin at 10 mg/kg, p.o. - 57.6% inhibition). When submitted to the carrageenan-induced peritonitis test, the AE (0.1, 0.3 and 1.0 g/kg, p.o.) impaired leukocyte migration into the peritoneal cavity by 24.8, 40.5 and 49.6%, respectively. The positive control, dexamethasone (2 mg/kg, s.c.), inhibited leukocyte migration by 66.9%. These results indicate the presence of anti-inflammatory and antinociceptive principles in the acetone extract of Anacardium occidentale, and reinforce the plants potential therapeutic use against pain and inflammatory diseases.

Evaluation of antinociceptive and antiinflammatory effects of Croton pullei var. glabrior Lanj. (Euphorbiaceae)

Croton pullei var. glabrior Lanj. (Euphorbiaceae) is a liana, vastly distributed in the Amazonian Forest. In the folk medicine, several plants of the Croton genus have been used with therapeutic purposes in pathologies that involve painful and inflammatory diseases which justify this work. The aim of this study was to investigate the antinociceptive and antiinflammatory activities of the C. pullei leaves methanol extract (MECP). MECP reduced in a dose-dependent manner the number of acetic acid-induced abdominal writhing (1.2%) in mice, suggesting an antinociceptive activity of the plant. On the other hand, MECP did not significantly modify the reactivity to the thermal stimulation in the hot-plate test and the reactivity to the chemical stimulation in the formalin test first phase, indicating a non-opioid mechanism. MECP reduced the formalin-induced nociception in the second phase, inhibited the croton oil-induced ear edema and reduced the leukocytes migration in the test of the carrageenan-induced peritonitis, indicating an antiinflammatory activity. Although the mechanisms that underlie these plant effects are not completely elucidated, these results appear to support the potential medicinal use of Croton pullei var. glabrior Lanj. against painful and inflammatory diseases.

Evaluation of analgesic and anti-inflammatory activities of Hydrocotyle umbellata L., Araliaceae (acariçoba) in mice.

The Hydrocotyle umbellata L. is a specimen of the Araliaceae family popularly known as acariçoba. Its indications in folk medicine include treatment of skin ulcers, and rheumatism. The aim of this study was to evaluate the antinociceptive and anti-inflammatory activities of the ethanolic extract from acariçobas underground parts (EEA). EEA reduced the nociceptive response of the animals as evaluated in the acetic acid-induced writhing test and in both phases of formalin test. EEA also presented a supraspinal analgesic activity by increasing the pain latency in the hot plate test. Moreover, EEA reduced the leukocytes migration and plasma extravasation to pleural cavity in the carrageenan-induced pleurisy, besides reducing the edema induced by carrageenan until the second hour and also the edema induced by dextran. In conclusion our results showed that EEA of H. umbellata L. presents analgesic and anti-inflammatory activities, and that a blockade of activity or reduction in the release of different mediators, such as histamine and serotonin, could be involved in these pharmacologic effects.

Antidepressive-Like Property of Dichloromethane Fraction of Pimenta pseudocaryophyllus and Relevance of Monoamine Metabolic Enzymes

Pimenta pseudocaryophyllus popularly referred to as craveiro is considered as a calming agent in different local preparations. The present study attempted to examine antidepressant-like effect of dichloromethane fraction (DF) and role of monoamine oxidase (MAO), tryptophan, and tyrosine hydroxylase. Based on the research focus, tail suspension (TS), forced swimming (FS), and open field (OF) tests were conducted after oral administration of DF (125, 250, or 500 mg/Kg). Ex vivo assay of MAO was also conducted to evaluate inhibitory effect of DF (250 mg/Kg). Administration of DF elicits antidepressant-like response in the TS and FS. However, DF 500 mg/Kg did not alter mice performance in these models. The data obtained in the OF showed a reduction in total crossing and rearing activity; these effects suggest motor interference in TS and FS performance. Mice pretreatment with p-chlorophenylalanine methyl ester (PCPA) (100 mg/kg, i.p.—serotonin biosynthesis inhibitor) for 4 consecutive days or acute administration of α-methyl-p-tyrosine (AMPT) (100 mg/kg, i.p.—catecholamine synthesis inhibitor) blocked anti-immobility effect of DF in the FS. In ex vivo assay of MAO, DF did not inhibit catabolic activity of MAO. Our findings support antidepressant-like activity of DF and suggest an effect that depends on monoamine biosynthesis.

Anxiolytic-like and sedative effects of Hydrocotyle umbellata L., Araliaceae, extract in mice

The plant Hydrocotyle umbellata L., Araliaceae (water pennywort), is widely used in Brazilian folk medicine to reduce anxiety. This work investigates the anxiolytic-like effects of the ethanol extract from H. umbellata subterraneous parts as well as the extracts other putative central nervous system effects that could justify its common use. Oral dosing of the extract (0.3 and 1 g/kg) clearly showed an anxiolytic-like profile in the elevated plus maze test where it increased the percentage of entries into and the time spent in the open arms of the maze. In the marble-burying test, the extract induced anxiolytic-like effects only at a dose of 1 g/kg, which also causes mild sedative properties in other models. The sedated state was characterized by a slight reduction in spontaneous exploratory activity during the open field test and a potentiating of pentobarbital-induced hypnosis. No signs of motor impairment were detected in the rota rod or chimney tests. The extract did not show antidepressant properties in mice as assessed by the forced swimming test. These results support the use of H. umbellata in Brazilian folk medicine as an anxiolytic and contribute to the scientific knowledge of this possible phytotherapeutic resource.

Involvement of the monoamine system in antidepressant-like properties of 4-(1-phenyl-1h-pyrazol-4-ylmethyl)-piperazine-1-carboxylic acid ethyl ester.

AIMS Piperazinic derivatives have therapeutic potential by acting as analgesic, antidepressant-like, anticonvulsant and antipsychotic in preclinical studies. In order to develop new drugs to treat mental disorders, we designed and synthesized the 4-(1-phenyl-1H-pyrazol-4-ylmethyl)-piperazine-1-carboxylic acid ethyl ester (PPMP), a new piperazine derivative with putative activities on central nervous system that seems to involve serotonergic system. MATERIALS AND METHODS In order to investigate the antidepressant-like activity of PPMP, mice were treated acutely and tested in the forced swimming test (FST) and tail suspension test. Pretreatment with the 5-HT synthesis inhibitor p-chlorophenylalanine (PCPA, 100 mg/kg, i.p., 4 days), and the non-selective blocker of catecholamine synthesis α-methyl para-tyrosine (AMPT, 100 mg/kg, i.p.) were used to assay the involvement of serotonergic and catecholaminergic systems. “Ex vivo” monoamine oxidase (MAO) enzymatic assay and quantification of hippocampal level of brain derived neurotrophic factor (BDNF) were carried out. KEY FINDINGS PPMP reduced the immobility time in both tests. PCPA or AMPT (100 mg/kg, i.p.) pretreatment blocked the effects of PPMP, thereby suggesting the involvement of serotonergic and catecholaminergic systems in the antidepressant-like effect of PPMP. PPMP did not inhibit the activity of MAO. Moreover, after 14 days of treatment, PPMP 15 mg/kg/day induced antidepressant-like effect and increased hippocampal level of BDNF. None of the treatments in this study altered the locomotor activity in the open field test. SIGNIFICANCE In conclusion, PPMP demonstrates antidepressant-like effect that involve both serotonergic and catecholaminergic systems without inhibition of MAO activity. PPMP administration increased the hippocampal levels of BDNF.

Sodium selenite supplementation during pregnancy and lactation promotes anxiolysis and improves mnemonic performance in wistar rats' offspring

Selenium is a micronutrient which is part of selenoprotein molecules and participates in a vast number of physiological roles and, among them,we have fetal and neonatal development. Therefore, the aimof this studywas to evaluate possible behavioral changes in offspring of female rats supplemented during pregnancy and lactation with sodium selenite. To address that, we treated two groups of female rats by saline or sodium selenite at a dose of 1mg/kg through oral route and performed neurochemical and behavioral tests. In the offspring, the thyroid profile and hippocampal neurochemistrywere evaluated. Behavioral testswere performed in pups both during childhood and adulthood. We found out that selenium (Se) supplementation increased serum levels of triiodothyronine (25%, p b 0.001) and thyroxine (18%, p b 0.05) and promoted a tryptophan hydroxylase 2 (TPH 2) expression decrease (17%, p b 0.01) and tyrosine hydroxylase (TH) expression increase (202%, p b 0.01) in the hippocampus. The cholinesterase activity was decreased (28%, p b 0.01) in Se supplemented rats, suggesting a neurochemical modulation in the hippocampal activity. During childhood, the Sesupplemented offspring had a reduction in anxiety-like behavior both in elevated plus maze test and in light–dark box test. In adulthood, Se-treated pups had an increase in the locomotor activity (36%, p b 0.05) and in rearing episodes (77%, p b 0.001) in the open field test, while in the elevated plus maze test they also exhibited an increase in the time spent in the open arms (243%, p b 0.01). For the object recognition test, Se-treated offspring showed increase in the absolute (230.16%, p b 0.05) and relative index discrimination (234%, p b 0.05). These results demonstrate that maternal supplementation by sodium selenite promoted psychobiological changes both during childhood and adulthood. Therefore, the behavioral profile observed possibly can be explained by neurochemical changes induced by thyroid hormones during the critical period of the central nervous system ontogeny.

Monoamine Involvement in the Antidepressant-Like Effect of β-Caryophyllene

BACKGROUND Major depressive disorder is a psychiatric disorder that affects 4.4% of the population worldwide. Although the majority of antidepressant drugs ameliorate depressive symptoms, there is still a need for safer and more effective antidepressant. OBJECTIVE Evaluate the antidepressant-like activity of sesquiterpene compound β-caryophyllene (BCP) for the possible contribution of the monoamine and hippocampal levels of brain-derived neurotrophic factor (BDNF). METHODS Male albino Swiss mice were subjected to the forced swimming test after acute treatment and to the tail suspension test after repeated treatment. Hippocampal levels of BDNF were assayed by enzyme-linked immunosorbent assay. RESULTS The anti-immobility effect of BCP was reverted by pretreatment with an inhibitor of catecholamine synthesis α-methyl-p-tyrosine (100 mg/kg, i.p.), α2-adrenergic antagonist yohimbine (1 mg/kg, i.p.), and β-adrenergic antagonist propranolol (2 mg/kg, i.p.), but not by pretreatment with either α1-adrenergic antagonist prazosin (1 mg/kg, i.p.) or 5-HT1A antagonist NAN-190 (0.5 mg/kg, i.p.), thereby suggesting the involvement of α2 and β-adrenergic receptors, but not of the α1-adrenergic and 5-HT1A serotonergic receptors, in BCPs antidepressive-like activity. Furthermore, BCP increased BDNF levels in the hippocampus after 14 days of treatment. No treatments in this study altered locomotor activity in the open field test. CONCLUSION This study provides a new mechanism of BCP-induced antidepressant-like effect mediated by some sub-types of catecholaminergic neurotransmitter system that could be a candidate for clinical tests of new treatments for depressive disorders.