Brinell Arcanjo Moura

Antinociceptive Effect of the Monoterpene R -(+)-Limonene in Mice

In the present study were studied the antinociceptives properties of monoterpene R-(+)-limonene (LM) in chemical and thermal models of nociception in mice. The R-(+)-limonene was administered, intraperitoneally (i.p.), at doses of 25 and 50 mg/kg. The results showed significant inhibition produced on chemical nociception induced by intraperitoneal acetic-acid and in the second phase of subplantar formalin test, but did not manifest a significant effect in hot-plate test. The R-(+)-limonene-induced antinociception in second phase of formalin test was insensitive to naloxone (1 mg/kg, s.c.). It was also demonstrated that R-(+)-limonene (25, 50 mg/kg) neither significantly enhanced the pentobarbital-sleeping time nor impaired the motor performance in rota-rod test, indicating that the observed antinociception is unlikely to be due to sedation or motor abnormality. In conclusion it may be suggested that the R-(+)-limonene presented antinociceptive activity and that, probably, this action can be related with peripheral analgesia, but, not with the stimulation of opioids receptors.

Central nervous system activity of acute administration of isopulegol in mice

Isopulegol is a monoterpene alcohol intermediate in the preparation of (-)-menthol and it is present in the essential oils of various plants. This work presents behavioral effects of isopulegol in animal models of open field, elevated plus maze (EPM), rota rod, hole board, barbiturate-induced sleeping time, tail suspension and forced swimming tests in mice. Isopulegol was administered intraperitoneally to male mice at single doses of 25 and 50 mg/kg, while diazepam 1 or 2 mg/kg and imipramine 10 or 30 mg/kg were used as standard drugs. The results showed that, similar to diazepam (1 mg/kg), both doses of isopulegol significantly modified all the observed parameters in the EPM test, without alter the general motor activity in the open field test. In the same way, both doses of isopulegol increased the number of head dips in the hole-board test. Forced swimming and tail suspension tests showed that isopulegol (25 and 50 mg/kg) was able to induce a significant increase in the immobility time, in opposite to imipramine, a recognized antidepressant drug. There was a decrease in the sleep latency time and prolongation of the pentobarbital-induced sleeping time with both doses of Isopulegol. Different from diazepam (2 mg/kg), isopulegol (25 e 50 mg/kg) had no effect on the motor coordination of animals in the rota rod test. These results showed that isopulegol presented depressant- and anxiolytic-like effects.

Behavioral alterations and pro-oxidant effect of a single ketamine administration to mice.

A growing body of evidence has pointed to the ionotropic glutamate N-methyl-d-aspartate receptor (NMDA) as an important player in the etiology of psychopathologies, including anxiety and major depression. Clinical findings suggest that ketamine may be used for the treatment of major depression. There is evidence that reactive oxygen species also play an important role in the pathogenesis of many diseases, particularly those which are neurological and psychiatric in nature. This study examined the behavioral and oxidative stress alterations after a single administration of ketamine (5, 10 and 20mg/kg i.p.) in mice. Ketamine presented a significant anxiogenic effect in the elevated plus-maze model of anxiety, also increasing locomotor activity. In the forced swimming and tail suspension tests, a significant decrease in immobility time after ketamine administration was observed. In addition to the behavioral changes induced by ketamine, this drug also increased lipid peroxidation, nitrite content and catalase activity, while decreased GSH levels in mice prefrontal cortex. In conclusion, our results confirm the antidepressant effects of ketamine, also showing a pro-oxidant effect of this drug.

Gastroprotective activity of isopulegol on experimentally induced gastric lesions in mice: investigation of possible mechanisms of action.

The present study investigated whether isopulegol, a monoterpene present in essential oils of several aromatic plants, would be able to promote some gastroprotective effect and also verified the possible mechanisms involved in this action. For this study, ethanol- and indomethacin-induced gastric ulcer models in mice and histopathological assessment were used. The roles of NO, sulfhydryls (glutathione, GSH), ATP-sensitive K+ channels (KATP channels), and prostaglandins were also investigated. Isopulegol exhibited a dose-related gastroprotective effect against ethanol-induced lesions, while the pretreatment with glibenclamide and indomethacin [but not with N(G)-nitro-l-arginine methyl ester] were able to reverse this action. The pretreatment with isopulegol also restored GSH levels to normal levels and exhibited dose-related gastroprotective effect against indomethacin-induced ulcer. The results suggested that isopulegol presents significant gastroprotective effects in both ethanol- and indomethacin-induced ulcer models, which appear to be mediated, at least in part, by endogenous prostaglandins, KATP channel opening, and antioxidant properties.

Antidepressant-like effect of carvacrol (5-Isopropyl-2-methylphenol) in mice: involvement of dopaminergic system

Carvacrol (5‐isopropyl‐2‐methylphenol) is a monoterpenic phenol present in the essential oil of many plants. It is the major component of the essential oil fraction of oregano and thyme. In this study, the effect of carvacrol was investigated in two behavioral models, the forced swimming and tail suspension tests in mice, to investigate the possible antidepressant effect of this substance. Additionally, the mechanisms involved in the antidepressant‐like effect of carvacrol in mice were also assessed. Carvacrol (cvc) was administered orally at single doses of 12.5, 25 and 50 mg/kg. The acute treatment of cvc decreased the immobility time in the forced swimming and tail suspension tests without accompanying changes in ambulation in the open‐field test. The anti‐immobility effect of carvacrol (25 mg/kg) was not prevented by pretreatment of mice with p‐chlorophenylalanine, prazosin and yohimbine. On the other hand, the pretreatment of mice with SCH23390 or sulpiride completely blocked the antidepressant‐like effect of carvacrol (25 mg/kg) in the forced swimming test. These results show that carvacrol presents antidepressant effects in the forced swimming and tail suspension tests; this effect seems to be dependent on its interaction with the dopaminergic system, but not with the serotonergic and noradrenergic systems. Keywords: Carvacrol; Antidepressant; Forced swimming; Tail suspension; Dopaminergic system.

Effects of isopulegol on pentylenetetrazol-induced convulsions in mice: possible involvement of GABAergic system and antioxidant activity.

The present study investigated the effects of isopulegol, a monoterpene alcohol, in PTZ-induced convulsions and verified possible involved mechanisms. Saline, isopulegol or diazepam were intraperitonealy injected 30 min before PTZ. The latency for development of convulsions and mortality, as well as the mortality protection percentage was recorded. For investigating the involvement of GABAergic system, flumazenil was utilized. The activity of antioxidant enzyme catalase as well as the levels of reduced glutathione and lipid peroxidation were measured in brain hippocampus. Similarly to diazepam, isopulegol significantly prolonged the latency for convulsions and mortality of mice. All animals were protected against mortality at higher dose of isopulegol. Flumazenil pretreatment decreased the prolongation of seizure latency induced by both diazepam and isopulegol, although it was not able to reverse the latency and protection percent for mortality. Isopulegol also significantly prevented PTZ-induced increase in lipid peroxidation, preserved catalase activity in normal levels, and prevented the PTZ-induced loss of GSH in hippocampus of mice. These results suggest that the anticonvulsant and bioprotective effects of isopulegol against PTZ-induced convulsions are possibly related to positive modulation of benzodiazepine-sensitive GABA(A) receptors and to antioxidant properties.

Gastroprotection of (-)-α-bisabolol on acute gastric mucosal lesions in mice: the possible involved pharmacological mechanisms

(‐)‐α‐Bisabolol is an unsaturated, optically active sesquiterpene alcohol obtained by the direct distillation essential oil from plants such as Vanillosmopsis erythropappa and Matricaria chamomilla. (‐)‐α‐Bisabolol has generated considerable economic interest, since it possesses a delicate floral odor and has been shown to have anti‐septic and anti‐inflammatory activity. The aim of this work was to evaluate the gastroprotective action of (‐)‐α‐bisabolol on ethanol and indomethacin‐induced ulcer models in mice, and further investigate the pharmacological mechanisms involved in this action. The oral administration of (‐)‐α‐bisabolol 100 and 200 mg/kg was able to protect the gastric mucosa from ethanol (0.2 mL/animal p.o.) and indomethacin‐induced ulcer (20 mg/kg p.o.). Administration of l‐NAME (10 mg/kg i.p.), glibenclamide (10 mg/kg i.p.) or indomethacin (10 mg/kg p.o.) was not able to revert the gastroprotection promoted by (‐)‐α‐bisabolol 200 mg/kg on the ethanol‐induced ulcer. Dosage of gastric reduced glutathione (GSH) levels showed that ethanol and indomethacin reduced the content of non‐protein sulfhydryl (NP‐SH) groups, while (‐)‐α‐bisabolol significantly decreased the reduction of these levels on ulcer‐induced mice, but not in mice without ulcer. In conclusion, gastroprotective effect on ethanol and indomethacin‐induced ulcer promoted by (‐)‐α‐bisabolol may be associated with an increase of gastric sulfydryl groups bioavailability leading to a reduction of gastric oxidative injury induced by ethanol and indomethacin.

Mechanisms involved in the gastroprotective activity of esculin on acute gastric lesions in mice.

This work describes the gastroprotective actions of esculin (6,7-dihydroxycoumarin-6-o-glucoside) against indomethacin- or ethanol-induced lesions and verifies the role of nitric oxide, ATP-dependent K(+) channels, prostaglandins, transient receptor potential vanilloid 1 and antioxidant effects in the gastroprotective mechanism of esculin in the ethanol-induced gastric lesion model. The intragastric administration of esculin at doses of 12.5, 25 and 50 mg/kg was able to protect the gastric mucosa against ethanol (0.2 mL/animal p.o.), and esculin at doses of 25 and 50 mg/kg protected against indomethacin-induced lesions (20mg/kg p.o.). Administration of l-NAME (10mg/kg i.p.), glibenclamide (10mg/kg i.p.) or indomethacin (10mg/kg p.o.), but not capsazepine (5mg/kg p.o.), was able to reduce the gastroprotection promoted by esculin (25mg/kg) on the ethanol-induced lesions. Measurements of nitrite, a NO metabolite, were increased in the group that was pretreated with esculin. In terms of antioxidant activity as a gastroprotective mechanism of esculin, the results show that pre-treatment with esculin decreased the amount of GSH, increased SOD activity, did not interfere with the CAT activity and decreased both the MPO activity and the MDA amount. In conclusion, pre-treatment with esculin confers significant gastroprotective and antioxidant activity and leads to a reduction in gastric injury; the mechanisms underlying these effects include stimulation of endogenous prostaglandins, nitric oxide synthesis, opening of K(ATP) channels and reduction of free radicals or modulation of antioxidant enzyme systems.

Anxiolytic-like effect of the monoterpene 1,4-cineole in mice

Recent studies have shown that some monoterpenes exert anxiolytic- and depressant-like actions, however, these effects from monoterpene 1,4-cineole are still unknown. This work aimed to study the effects of 1,4-cineole in classic animal models for depression- and anxiety-like behavior, specifically the elevated plus maze (EPM), hole board, open field, pentobarbital sleeping time, forced swimming, tail suspension and rota rod tests. 1,4-Cineole was administered orally to mice (100, 200 and 400 mg/kg), while diazepam (1 or 2 mg/kg) and imipramine (10 or 30 mg/kg) were used as standard drugs. 1,4-Cineole (400 mg/kg) modified all parameters observed in the EPM, while no significant variation was observed on general motor activity in the open-field test. In the hole-board assay, 1,4-cineole induced increase on the number of head dips. Forced swimming and tail suspension tests showed that cineole (200 and/or 400 mg/kg) was able to promote significant increase on the immobility time, while a decreased sleep latency was observed (200 and 400 mg/kg ) on the pentobarbital sleeping time. Cineole had no effect on the motor coordination of animals in the rota rod test. The results suggest that 1,4-cineole presents potential anxiolytic-like action consistent with possible general depression of the CNS.

Effects of hecogenin and its possible mechanism of action on experimental models of gastric ulcer in mice.

This study investigates the gastroprotective effects of hecogenin, a steroid saponin isolated from Agave sisalana, on experimental models of gastric ulcer. Male Swiss mice were used in the models of ethanol- and indometacin-induced gastric ulcer. To clarify the hecogenin mechanism of action, the roles of nitric oxide (NO), sulfhydryls (GSH), K⁺(ATP) channels and prostaglandins were also investigated, and measurements of lipid peroxidation (TBARS assay) and nitrite levels in the stomach of hecogenin-treated and untreated animals were performed. Furthermore, the effects of hecogenin on myeloperoxidase (MPO) release from human neutrophils were assessed in vitro. Our results showed that hecogenin (3.1, 7.5, 15, 30, 60 and 90 mg/kg, p.o.) acutely administered, before ethanol or indomethacin, exhibited a potent gastroprotective effect. Although the pretreatments with L-NAME, an iNOS inhibitor, and capsazepine, a TRPV1 receptor agonist, were not able to reverse the hecogenin effect, this was reversed by glibenclamide, a K⁺(ATP) blocker, and indomethacin in the model of ethanol-induced gastric lesions. The hecogenin pretreatment normalized GSH levels and significantly reduced lipid peroxidation and nitrite levels in the stomach, as evaluated by the ethanol-induced gastric lesion model. The drug alone increased COX-2 expression and this effect was further enhanced in the presence of ethanol. It also decreased MPO release and significantly protected the gastric mucosa. In conclusion, we showed that hecogenin presents a significant gastroprotective effect that seems to be mediated by K⁺(ATP) channels opening and the COX-2/PG pathway. In addition, its antioxidant and anti-inflammatory properties may play a role in the gastroprotective drug effect.