Iziara Ferreira Florentino

The anxiolytic-like effect of an essential oil derived from Spiranthera odoratissima A. St. Hil. leaves and its major component, β-caryophyllene, in male mice

Spiranthera odoratissima A. St. Hil. (manacá) is used in folk medicine to treat renal and hepatic diseases, stomachache, headaches and rheumatism. A central nervous system (CNS) depressant effect of the hexane fraction from the ethanolic extract of this plant has been described. β-caryophyllene, the main component of this essential oil, is a sesquiterpene compound with anti-inflammatory properties that has been found in essential oils derived from several medicinal plants. This work is aimed to evaluate the pharmacological activity of the essential oil obtained from S. odoratissima leaves (EO) and its major component on the murine CNS; we aimed to evaluate a possible anxiolytic-like effect and the underlying mechanisms involved. In an open field test, EO (500 mg/kg) and β-caryophyllene (50, 100 and 200 mg/kg) increased the crossing frequency (P<0.05) and, EO (250 and 500 mg/kg) and β-caryophyllene (200 mg/kg) increased the time spent in the center (P<0.05) without altering total crossings of the open field. EO and β-caryophyllene did not alter the number of falls in the rota-rod test (P>0.05). In the pentobarbital-induced sleep test, EO (500 mg/kg) and β-caryophyllene (200 and 400 mg/kg) decreased the latency to sleep (P<0.05), and EO (125, 250 and 500 mg/kg) (P<0.001) and β-caryophyllene (200 and 400 mg/kg) (P<0.05 and P<0.001) increased the sleep time. In anxiety tests, EO (500 mg/kg) and β-caryophyllene (100 and 200 mg/kg) increased head-dipping behavior (P<0.05) in the hole-board test, entries (P<0.05) into and time spent (P<0.05) on the open arms of the elevated plus maze (EPM), and number of transitions (P<0.05) and time spent in the light compartment (P<0.05) of a light-dark box (LDB). We further investigated the mechanism of action underlying the anxiolytic-like effect of EO and β-caryophyllene by pre-treating animals with antagonists of benzodiazepine (flumazenil) and 5-HT(1A) (NAN-190) receptors prior to evaluation using EPM and LDB. The anxiolytic-like effects of EO were significantly reduced by pre-treatment with NAN-190 (P<0.05) but not flumazenil (P>0.05). The anxiolytic-like effects of β-caryophyllene were not blocked by either NAN-190 or flumazenil (P>0.05). In conclusion, these results suggest that the essential oil derived from S. odoratissima produces an anxiolytic-like effect without altering motor performance and that this effect is mediated by 5-HT(1A) but not via benzodiazepine receptors. In addition, the major component, β-caryophyllene, also has an anxiolytic-like effect that may contribute to the effects of EO, but this effect does not seem to be mediated via 5-HT(1A) or benzodiazepine receptors.

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.

Antinociceptive, anti-inflammatory and antipyretic effects of 1.5-diphenyl-1H-Pyrazole-3-carbohydrazide, a new heterocyclic pyrazole derivative

AIMS Heterocyclic pyrazole derivative has been described for the treatment of pain and inflammatory diseases. This study evaluated the in vivo, antinociceptive, anti-inflammatory and antipyretic effects of 1.5-diphenyl-1H-Pyrazole-3-carbohydrazide (1.5-DHP) and the in vivo or in vitro mechanism of action. MAIN METHODS Acetic acid-induced writhing, hot-plate and formalin-induced nociception tests were used to evaluate the antinociceptive effect, while the rota-rod test was used to assess the motor activity. Croton oil-induced ear edema and carrageenan-induced peritonitis tests were used to investigate the anti-inflammatory effect of 1.5-DHP. The antipyretic effect was assessed using the LPS-induced fever model. The mechanism of action was evaluated by PGE2 and TNF-α measurement and cyclooxygenase inhibition assay. KEY FINDINGS Oral administration (p.o.) of 1.5-DHP (1, 3, 10 mg/kg) caused a dose-related inhibition of the acetic acid-induced writhing, however the highest dose was not effective on the hot-plate and rota-rod. In the formalin-induced nociception, 1.5-DHP (10mg/kg, p.o.) inhibited only the late phase of nociception. This same dose of 1.5-DHP also reduced the croton oil-induced ear edema. 1.5-DHP (3, 10, 30 mg/kg, p.o.) produced a dose-related reduction of leukocyte migration on the carrageenan-induced peritonitis. 1.5-DHP (60 mg/kg, p.o.) reduced the fever and the increase of PGE2 concentration in the cerebrospinal fluid induced by LPS. 1.5-DHP inhibited both COXs in vitro. Finally, 1.5-DHP (10 mg/kg, p.o.) reduced the TNF-α concentration in peritoneal exudates after carrageenan injection. SIGNIFICANCE These results indicate that 1.5-DHP produces anti-inflammatory, antinociceptive and antipyretic effects by PGE2 synthesis reduction through COX-1/COX-2 inhibition and by TNF-α synthesis/release inhibition.

Involvement of the NO/cGMP/KATP pathway in the antinociceptive effect of the new pyrazole 5-(1-(3-fluorophenyl)-1H-pyrazol-4-yl)-2H-tetrazole (LQFM-021)

The pyrazol compounds are known to possess antipyretic, analgesic and anti-inflammatory activities. This study was conducted to investigate the peripheral antinociceptive effect of the pyrazole compound 5-(1-(3-Fluorophenyl)-1H-pyrazol-4-yl)-2H-tetrazole (LQFM-021) and involvement of opioid receptors and of the NO/cGMP/K(ATP) pathway. The oral treatments in mice with LQFM-021 (17, 75 or 300 mg/kg) decreased the number of writhing. In the formalin test, the treatments with LQFM-021 at doses of 15, 30 and 60 mg/kg reduced the licking time at both neurogenic and inflammatory phases of this test. The treatment of the animals with LQFM-021 (30 mg/kg) did not have antinociceptive effects in the tail-flick and hot plate tests. Furthermore, pre-treatment with naloxone (3 mg/kg i.p.), L-name (10 mg/kg i.p.), ODQ (10 mg/kg i.p.) or glibenclamide (3 mg/kg i.p.) antagonized the antinociceptive effect of LQFM-021 in both phases of the formalin test. In addition, it was also demonstrated that the treatments of mice with LQFM-021(15, 30 and 60 mg/kg) did not compromise the motor activity of the animals in the chimney test. Only the highest dose used in the antinociceptive study promoted changes in the open field test and pentobarbital-induced sleep test, thus ruling out possible false positive effects on nociception tests. Our data suggest that the peripheral antinociception effects of the LQFM-021 were mediated through the peripheral opioid receptors with activation of the NO/cGMP/KATP pathway.

Anti-inflammatory and antinociceptive activities of LQFM002 - A 4-nerolidylcatechol derivative.

AIMS The current study describes the synthesis and pharmacological evaluation of (E)-N-(3,7-dimethylocta-2,6-dienyl)-1,3-dimethyl-1H-pyrazol-5-amine (LQFM002), a compound originally designed through a molecular simplification strategy from 4-nerolidylcatechol. LQFM002 was evaluated for preservation of the PLA(2) enzyme inhibitory effects of the lead compound, 4-nerolidylcatechol, using in vitro and in vivo models. MAIN METHODS Rota-rod, open field and pentobarbital-induced sleeping tests were used to evaluate the effects of LQFM002 on the central nervous system. A gel plate assay of PLA(2) activity, carrageenan-induced pleurisy and TNF-α levels was used to assay anti-inflammatory activity. Antinociceptive activities of LQFM002 were evaluated with acetic acid-induced writhing, formalin and hot-plate tests, while involvement of the opioid pathway in the LQFM002 antinociceptive effect was investigated with naloxone pre-treatment. KEY FINDINGS LQFM002 inhibited PLA(2) activity, cell migration into the pleural cavity, and capillary permeability (Evans blue concentration) and reduced TNF-α levels in pleural exudates. LQFM002 also reduced acetic acid-induced writhing and the licking time in both phases of the formalin test and increased latency in the hot-plate test. Pre-treatment with 8.25 μmol/kg naloxone (3mg/kg) reversed the analgesic effects of LQFM002 in the early phase of the formalin test. SIGNIFICANCE LQFM002 showed anti-inflammatory activity, which possibly involved reduction of leukocyte migration and TNF-α levels. LQFM002 also demonstrated inhibition of PLA(2) activity in vitro. LQFM002 had an antinociceptive effect that involved the opioidergic system.

Mechanisms Underlying the Antinociceptive, Antiedematogenic, and Anti-Inflammatory Activity of the Main Flavonoid from Kalanchoe pinnata

Kalanchoe pinnata (KP) is popularly used for treating inflammatory diseases. This study investigated the antinociceptive, antiedematogenic, and anti-inflammatory potential of the subcutaneous administration of KP flower aqueous extract (KPFE), its ethyl acetate (EtOAcF) and butanol (BuOHF) fractions, and the main KP flavonoid [quercetin 3-O-α-L-arabinopyranosyl (1 → 2) α-L-rhamnopyranoside] (KPFV) in mice, as well as its possible mechanisms of action. KPFE (30–300 mg/kg) and KPFV (1–10 mg/kg) inhibited the acetic acid-induced writhing (ID50 = 164.8 and 9.4 mg/kg, resp.). KPFE (300 mg/kg), EtOAcF (12 mg/kg), BuOHF (15 mg/kg), or KPFV (0.3–3.0 mg/kg) reduced leukocyte migration on carrageenan-induced pleurisy (ID50 = 2.0 mg/kg for KPFV). KPFE (3–30 mg/kg) and KPFV (0.3–3.0 mg/kg) reduced the croton oil-induced ear edema (ID50 = 4.3 and 0.76 mg/kg, resp.). KPFE and KPFV reduced the TNF-α concentration in the pleural exudates on carrageenan-induced pleurisy test. Moreover, KPFV inhibited COX-1 (IC50 = 22.1 μg/mL) and COX-2 (IC50 > 50 μg/mL). The selectivity index (COX-1IC50/COX-2IC50) was <0.44. These results indicate that KPFE and KPFV produced antinociceptive, antiedematogenic, and anti-inflammatory activities through COX inhibition and TNF-α reduction, revealing that the main flavonoid in KP flowers and leaves plays an important role in the ethnomedicinal use of the plant.

Antinociceptive effect of Lafoensia pacari A. St.-Hil. independent of anti-inflammatory activity of ellagic acid.

This study was performed to determine the antinociceptive and anti-inflammatory activities of ethanolic extract of Lafoensia pacari A. St.-Hil. (PEtExt) stem bark and its fractions using various animal models such as acetic acid-induced abdominal writhing, formalin-induced pain and croton oil-induced ear edema tests. The PEtExt inhibited the acetic acid-induced abdominal writhing, reduced the pain reaction time on both phases of the formalin test and decreased the edema in a dose-dependent manner. Pre-treatment with naloxone did not reverse the antinociceptive effect. Only the ethyl acetate fraction showed antinociceptive and anti-inflammatory effects. Our results also showed that this extract contains compounds with analgesic action independent of anti-inflammatory activity.

Antinociceptive and anti-inflammatory effects of Memora nodosa and allantoin in mice

ETHNOPHARMACOLOGICAL RELEVANCE The leaves and stems bark of Memora nodosa (Silva Manso) Miers (Bignoniaceae) are used in Brazilian traditional medicine in the treatment of external ulcers and wounds; its roots are used to treat abdominal pain and scabies. AIM OF THE STUDY Our aim was to evaluate the antinociceptive and anti-inflammatory activities of Memora nodosa roots ethanolic extract (EMN) and allantoin, a secondary metabolite isolated from this plant. MATERIALS AND METHODS The EMN and allantoin antinociceptive activity were evaluated in mice using both chemical and heat-induced pain models such as acetic acid-induced writhing, formalin and tail-flick tests. In the formalin test, a pre-treatment with naloxone was used to verify an involvement of opioid receptor in the antinociceptive effect of EMN and allantoin. Pre-treatment with glibenclemide was used to verity an involvement of ATP-sensitive K(+)channel in the allantoin antinociceptive effect. EMN and allantoin anti-inflammatory activity were assessed by carrageenan-induced paw edema and pleurisy tests. RESULTS The treatment with EMN (250, 500 and 1000mg/kg, p.o.) inhibit the acetic acid and formalin (both phases)-induced nociception. However, just at doses 500 and 1000mg/kg increased the latency time in tail-flick test. These results suggest the involvement of both peripheral and central antinociceptive mechanisms. The treatment with allantoin (40, 60 and 80mg/kg p.o.) produced a dose-dependent antinociceptive effect in both phases of formalin-induced nociception test; allantoin (60mg/kg) was not able to increase the latency time in tail flick-test. The pre-treatment with naloxone completely reversed the EMN (1000mg/kg) and allantoin (60mg/kg) effect in the first phase of formalin test; and glibenclamide reversed the allantoin effect. The administration of EMN (250, 500 and 1000mg/kg) and allantoin (60mg/kg) showed significant anti-inflammatory activity in the whole carrageenan-induced paw edema. Furthermore, EMN and allantoin reduced the leukocytes migration and pleural exudate to the pleural cavity. CONCLUSION EMN have significant antinociceptive and anti-inflammatory effects, which appear to be, at least in part, due to the presence of allantoin. However, allantoin is not responsible for the EMN central antinociceptive activity. Allantoin has peripheral antinociceptive activity that involves the opioid receptor and ATP-sensitive K(+)channels. Opioid receptors are also involved in the EMN antinociceptive activity. These findings support the use of Memora nodosa in popular medicine and demonstrate that this plant has therapeutic potential for the development of antinociceptive and anti-inflammatory phytomedicines.

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.

Medicinal species with gastroprotective activity found in the Brazilian Cerrado.

Peptic and/or duodenal ulcers are characterized by diverse acute and chronic ulcerative lesions that commonly arise in any portion of the gastric mucosa that is exposed to the aggressive action of gastric acid. The pathophysiology of peptic ulcers has been attributed to an imbalance between aggressive and protective factors. In Brazil, medicinal plants are commonly used to treat this ailment. A country with great biodiversity, Brazil is considered a rich source of therapeutic products. There have been popular and pharmacological reports on the medicinal relevance of the Brazilian cerrado plant species, including Ananas ananassoides, Celtis iguanaea, Encholirium spectabile, Hymenaea stigonocarpa, Lafoensia pacari, Qualea grandiflora, Qualea parvifora, Mouriri pusa, Solanum lycocarpum, Solanum paniculatum, Serjania erecta, and Vochysia tucanorum, in the treatment of stomach disorders. The aim of the present review was to report on some of the Brazilian cerrado plants that are used in folk medicine because of their gastroprotective potential and to encourage novel studies in the search and preservation of plants with this therapeutic potential.