Antinociceptive and anticonvulsant effects of the monoterpene linalool oxide.

CONTEXT: Linalool oxide (OXL) (a monoterpene) is found in the essential oils of certain aromatic plants, or it is derived from linalool. The motivation for this work is the lack of psychopharmacological studies on this substance. OBJECTIVE: To evaluate OXL's acute toxicity, along with its anticonvulsant and antinociceptive activities in male Swiss mice. MATERIAL AND METHODS: OXL (50, 100 and 150 mg/kg, i.p.) was investigated for acute toxicity and in the Rota-rod test. Antinociceptive activity was evaluated by the acetic acid-induced writhing test, and by formalin testing. Anticonvulsant effects were demonstrated by testing for pentylenetetrazol (PTZ)-induced seizures and by Maximum Electroshock headset (MES) test. OXL was administered to the animals intraperitoneally 30 min before for pharmacological tests. RESULTS: OXL showed an LD50 of ∼721 (681-765) mg/kg. In the Rota-rod test, it was observed that OXL caused no damage to the animal's motor coordination. OXL significantly reduced (p < .001) the number of writhings. OXL also significantly decreased (p < .05, p < .01 or p < .001) paw-licking time in the two phases of the formalin test. OXL significantly reduced (p < .01 or p < .001) the duration of tonic seizures in the MES test, and at the dose 150 mg/kg, significantly increased (p < .01) the latency to first seizure in the PTZ test. CONCLUSION: The tested doses of OXL were safe, with no motor impairment, and show clear antinociceptive and anticonvulsant potential. Future investigations with this monoterpene may lead to the development of a new molecule with even higher potency and selectivity.

Comparative Anticonvulsant Study of Epoxycarvone Stereoisomers.

Stereoisomers of the monoterpene epoxycarvone (EC), namely (+)-cis-EC, (-)-cis-EC, (+)-trans-EC, and (-)-trans-EC, were comparatively evaluated for anticonvulsant activity in specific methodologies. In the pentylenetetrazole (PTZ)-induced anticonvulsant test, all of the stereoisomers (at 300 mg/kg) increased the latency to seizure onset, and afforded 100% protection against the death of the animals. In the maximal electroshock-induced seizures (MES) test, prevention of tonic seizures was also verified for all of the isomers tested. However, the isomeric forms (+) and (-)-trans-EC showed 25% and 12.5% inhibition of convulsions, respectively. In the pilocarpine-induced seizures test, all stereoisomers demonstrated an anticonvulsant profile, yet the stereoisomers (+) and (-)-trans-EC (at 300 mg/kg) showed a more pronounced effect. A strychnine-induced anticonvulsant test was performed, and none of the stereoisomers significantly increased the latency to onset of convulsions; the stereoisomers probably do not act in this pathway. However, the stereoisomers (+)-cis-EC and (+)-trans-EC greatly increased the latency to death of the animals, thus presenting some protection. The four EC stereoisomers show promise for anticonvulsant activity, an effect emphasized in the isomers (+)-cis-EC, (+)-trans-EC, and (-)-trans-EC for certain parameters of the tested methodologies. These results serve as support for further research and development of antiepileptic drugs from monoterpenes.

Antinociceptive effect of hydantoin 3-phenyl-5-(4-ethylphenyl)-imidazolidine-2,4-dione in mice.

Imidazolidine derivatives, or hydantoins, are synthetic compounds with different therapeutic applications. Many imidazolidine derivatives have psychopharmacological properties, such as phenytoin, famous for its anticonvulsant efficacy, but also effective in the treatment of neuropathic pain. The hydantoin, 3-phenyl-5-(4-ethylphenyl)-imidazolidine-2,4-dione (IM-3), synthesized from the amino acid, glycine, was selected for psychopharmacological studies in mice on the basis of its chemical and structural similarity with phenytoin. The first step of this study was to define the LD50, which determined the doses of 50, 100 and 200 mg/kg for subsequent tests. The results obtained from the behavioral screening indicated that IM-3 produces decreased ambulation and analgesia in mice. Motor coordination and anxiety behavior were not affected by treatment with IM-3, as observed in the rotarod and elevated plus-maze tests, respectively. Regarding its antinociceptive properties, IM-3 showed efficacy in the acetic acid-induced writhing test by increasing the latency of the first writhe and reducing the number of writhes, as well as reducing the paw licking time in the second phase of the formalin test. The behavior of treated animals exposed to the hot plate test, however, did not differ from that of the control group. These data suggest that IM-3 has antinociceptive effects in mice, which is probably mediated by anti-inflammatory mechanisms.

Curine, an alkaloid isolated from Chondrodendron platyphyllum inhibits prostaglandin E2 in experimental models of inflammation and pain.

Curine is a bisbenzylisoquinoline alkaloid that is isolated from Chondrodendron platyphyllum, a plant that is used to treat malaria, inflammation, and pain. Recent reports have demonstrated the antiallergic effects of curine at nontoxic doses. However, its anti-inflammatory and analgesic properties remain to be elucidated. This study investigated the anti-inflammatory and analgesic effects of curine in mice. We analyzed the effects of an oral treatment with curine in the formation of paw edema, vascular permeability, abdominal contortion, licking behavior, and hyperalgesia using different inflammatory stimuli. Curine significantly inhibited the formation of paw edema by decreasing vascular permeability, inhibited the acetic acid-induced writhing response, inhibited the licking behavior during inflammation but not during the neurogenic phase of the formalin test, and inhibited carrageenan-induced hyperalgesia. Finally, curine inhibited prostaglandin E2 production in vitro without affecting cyclooxygenase-2 expression. The effects of curine treatment were similar to the effects of indomethacin, but were different from the effects of morphine treatment, suggesting that the analgesic effects of curine do not result from the direct inhibition of neuronal activation but instead depend on anti-inflammatory mechanisms that, at least in part, result from the inhibition of prostaglandin E2 production. In conclusion, curine presents anti-inflammatory and analgesic effects at nontoxic doses and has the potential for use in anti-inflammatory drug development.

Comparison of behavioral, neuroprotective, and proinflammatory cytokine modulating effects exercised by (+)-cis-EC and (-)-cis-EC stereoisomers in a PTZ-induced kindling test in mice.

Epoxy-carvone (EC) has chiral centers that allow generation of stereoisomers, including (+)-cis-EC and (-)-cis-EC, whose effects in the kindling tests have never been studied. Accordingly, this study aims to comparatively investigate the effect of stereoisomers (+)-cis-epoxy-carvone and (-)-cis-epoxy-carvone on behavioral changes measured in scores, in the levels of cytokines (IL-1ß, IL-6, and TNFα) and neuronal protection in the face of continuous treatment with pentylenetetrazol. Swiss mice were divided into five groups (n = 10), receiving vehicle, (+) - cis-EC, (-) - cis-EC (both at the dose of 30 mg/kg), and diazepam (4 mg/kg). Thirty minutes after the respective treatment was administered to the animals one subconvulsive dose of PTZ (35 mg/kg). Seven subconvulsives treatments were made on alternate days, in which each treatment several parameters were recorded. In the eighth treatment, the animals receiving the highest dose of PTZ (75 mg/kg) and were sacrificed for quantification of cytokines and histopathologic analysis. All drugs were administered by intraperitoneal route. In the kindling test, (+)-cis-EC and (-)-cis-EC reduced the average scores. The stereoisomer (+)-cis-EC decreased levels of proinflammatory cytokines IL-1ß, IL-6, and TNFα, whereas comparatively (-)-cis-EC did not reduce IL-1ß levels. Histopathological analysis of the mice hippocampi undergoing this methodology showed neural protection for treated with (+)-cis-EC. The results suggest that the anticonvulsant effect of (+)-cis-EC possibly takes place due to reduction of proinflammatory cytokines involved in the epileptogenic process, besides neuronal protection, yet further investigation of the mechanisms involved is required.

Anticonvulsive activity of (1S)-(-)-verbenone involving RNA expression of BDNF, COX-2, and c-fos.

(1S)-(-)-verbenone (VRB) is a monoterpene present in the essential oils of many plants which has shown therapeutic effect; however, its anticonvulsant activity has not yet been evaluated. The present work sought to investigate the anticonvulsant activity of VRB using pilocarpine and pentylenetetrazole-induced seizure testing; seeking also probable mechanisms of action. VRB caused no significant changes in motor coordination. Also, no significant data was observed in the pilocarpine-induced seizure tests. In the PTZ-induced seizures test, VRB showed anticonvulsant activity at doses of 200 mg/kg i.p. (733 ± 109.4 s) and 250 mg/kg i.p. (648.8 ± 124.5 s) significantly increasing the latency to onset of first seizure as compared with the vehicle group (51.8 ± 2.84 s). Pretreatment with flumazenil (FLU) did not reverse the anticonvulsive effect of VRB; however, it was able to upregulate BDNF and COX-2 genes and downregulate c-fos. The findings suggest that the anticonvulsant effects of VRB may be related to RNA expression modulations of COX-2, BDNF, and c-fos.

Antinociceptive activity of Sargassum polyceratium and the isolation of its chemical components

Abstract Marine algae have been the focus of important studies over the past fifty years, with a considerable number of components important to chemists and taxonomists having been isolated and characterized. The scientific data available on Sargassum polyceratium are extremely limited. The objective of the present study was to evaluate the antinociceptive activity of an ethanol extract of S. polyceratium and to isolate its components. Intraperitoneal treatment with ethanol extract of S. polyceratium reduced the number of acetic acid-induced writhes and the amount of time spent in paw-licking in the second phase of the formalin test. Ethanol extract of S. polyceratium also reduced the amount of time spent in paw-licking in the glutamate test; however, there was no difference in the reaction time in the hot plate test at any of the doses tested. The chemical components isolated from ethanol extract of S. polyceratium were identified using one- and two-dimensional spectroscopic methods such as infrared spectroscopy, mass spectrometry and 1H and 13C nuclear magnetic resonance spectroscopy. The analytical results were also compared with data obtained in the literature. The following porphyrin derivatives were isolated from S. polyceratium: 132-hydroxy-(132-R)-pheophytin-a, 132-hydroxy-(132-S)-pheophytin-a, pheophytin-a, and the steroid fucosterol. The present results indicate that the ethanol extract of S. polyceratium has antinociceptive activity. In addition, four new substances were isolated from the species evaluated.