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Background Currently there is a high prevalence of humor disorders such as anxiety and depression throughout the world, especially concerning advanced age patients. Aniba riparia (Nees) Mez. (Lauraceae), popular known as “louro”, can be found from the Amazon through Guianas until the Andes. Previous studies have already reported the isolation of alkamide-type alkaloids such as riparin III (O-methyl-N-2,6-dyhydroxy-benzoyl tyramine) which has demonstrated anxiolytic and antidepressant-like effects in high doses by intraperitoneal administration. Methods Experimental protocol was conducted in order to analyze the anxiolytic-like effect of riparin III at lower doses by intravenous administration to Wistar rats (Rattus norvegicus) (n = 5). The experimental approach was designed to last 15 days, divided in 3 distinct periods of five days: control, anxiogenic and treatment periods. The anxiolytic-like effect was evaluated by experimental behavior tests such as open field and elevated plus-maze test, combined with urine metabolic footprint analysis. The urine was collected daily and analyzed by 1H NMR. Generated data were statistically treated by Principal Component Analysis in order to detect patterns among the distinct periods evaluated as well as biomarkers responsible for its distinction. Results It was observed on treatment group that cortisol, biomarker related to physiological stress was reduced, indicating anxiolytic-like effect of riparin III, probably through activation of 5-HT2A receptors, which was corroborated by behavioral tests. Conclusion 1H NMR urine metabolic footprint combined with multivariate data analysis have demonstrated to be an important diagnostic tool to prove the anxiolytic-like effect of riparin III in a more efficient and pragmatic way.

Episodic-like memory (ELM) consists in the capacity of nonhuman animals to remember 'where' and 'when' a specific episode occurred ('what'). Previous studies have showed that Wistar rats can form an ELM, but not after a 24 h retention delay. On the other hand, it has been demonstrated that caffeine can improve episodic memory consolidation in humans. Therefore, we verified whether acute post-sample caffeine administration could improve ELM consolidation in Wistar rats, as well if it could be related to neurochemical changes in the prefrontal cortex and hippocampus - regions related to episodic-like memory processing. 46 Male Wistar Rats, approximately 3 months-old, were divided into four groups as follows: untreated (n = 11), saline (n = 11), caffeine 10 mg ∕kg i.p (n = 12); caffeine 15 mg∕kgi.p (n = 12) and tested in WWWhen/ELM task. The animals treated with caffeine in different dosages (10 mg/kg and 15 mg/kg) discriminated temporally and spatially the objects, respectively. These groups also showed a dopamine renewal rate in the hippocampus, suggesting that there was an increase in the turnover compared with the groups with no caffeine administration. We can conclude that caffeine leads to an improvement in the consolidation of the temporal ('what-when') and spatial ('what-where') aspects of episodic-like memory.

This study evaluated the orofacial antinociceptive effect of (S)-(-)-perillyl alcohol (PA) associated with codeine (C) and investigated the possible molecular anchorage mechanisms of PA. Mice (n = 5 per group) were treated with PA alone and associated with codeine and assigned to the following groups: 75.0 mg/kg PA; 75.0 mg/kg PA + C 30 mg/kg; PA 37.5 mg/kg + C 15.0 mg/kg; C 30.0 mg/kg; and control. Nociception was induced by formalin, capsaicin, and glutamate, and was quantified based on the duration (in seconds) of face grooming. The possible mechanisms of action were evaluated by molecular docking study. In the formalin test, PA75/C30 presented an effect in the neurogenic (p < 0.0001) and inflammatory (p < 0.005) phases. Mice treated with PA75 (p < 0.0001) and PA75/C30 (p < 0.0005) showed a reduced nociceptive behavior in the capsaicin test. Glutamate-induced nociception also was blocked by PA75 (p < 0.0005) and C30 (p < 0.0005). The molecular anchorage analysis indicated high negative binding energy values for the evaluated receptors, especially glutamate receptors (AMPA -79.57 Kcal/mol, mGLUR6 -71.25, and NMDA -66.33 Kcal/mol). PA associated with codeine showed orofacial antinociceptive activity, with theoretical evidence of interaction with glutamate receptors.

Epilepsy is a chronic neurological disorder affecting 1-2% of world population, and one-third of patients are refractory to pharmacological treatment. This fact has stimulated research for new antiepileptic drugs and natural products have been an important source.

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-1β, 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-1β, IL-6, and TNFα, whereas comparatively (-)-cis-EC did not reduce IL-1β 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.

(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.

Trypanosoma species are responsible for chronic and systemic infections in millions of people around the world, compromising life quality, and family and government budgets. This group of diseases is classified as neglected and causes thousands of deaths each year. In the present study, the trypanocidal effect of a set of 12 ester derivatives of the p-coumaric acid was tested. Of the test derivatives, pentyl p-coumarate (7) (5.16 &plusmn, 1.28 &mu, M, 61.63 &plusmn, 28.59 &mu, M) presented the best respective trypanocidal activities against both epimastigote and trypomastigote forms. Flow cytometry analysis revealed an increase in the percentage of 7-AAD labeled cells, an increase in reactive oxygen species, and a loss of mitochondrial membrane potential, indicating cell death by necrosis. This mechanism was confirmed by scanning electron microscopy, noting the loss of cellular integrity. Molecular docking data indicated that of the chemical compounds tested, compound 7 potentially acts through two mechanisms of action, whether by links with aldo-keto reductases (AKR) or by comprising cruzain (CZ) which is one of the key Trypanosoma cruzi development enzymes. The results indicate that for both enzymes, van der Waals interactions between ligand and receptors favor binding and hydrophobic interactions with the phenolic and aliphatic parts of the ligand. The study demonstrates that p-coumarate derivatives are promising molecules for developing new prototypes with antiprotozoal activity.

Made available in DSpace on 2019-10-06T16:45:21Z (GMT). No. of bitstreams: 0 Previous issue date: 2019-11-01 Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) Financiadora de Estudos e Projetos The search for new drugs with anti-inflammatory properties remains a challenge for modern medicine. Among the various strategies for drug discovery, deriving new chemical entities from known bioactive natural and/or synthetic compounds remains a promising approach. Here, we designed and synthesized CVIB, a codrug developed by association of carvacrol (a phenolic monoterpene) with ibuprofen (a non-steroidal anti-inflammatory drug). In silico pharmacokinetic and physicochemical properties evaluation indicated low aqueous solubility (LogP ≥5.0). Nevertheless, the hybrid presented excellent oral bioavailability, gastrointestinal tract absorption, and low toxicity. CVIB did not present cytotoxicity in peripheral blood mononuclear cells (PBMCs), and promoted a significant reduction in IL-2, IL-10, IL-17, and IFN-γ cytokine levels in vitro. The LD50 was estimated to be approximately 5000 mg/kg. CVIB was stable and detectable in human plasma after 24 h. In vivo anti-inflammatory evaluations revealed that CVIB at 10 and 50 mg/kg i.p. caused a significant decrease in total leukocyte count (p < 0.01) and provoked a significant reduction in IL-1β (p < 0.01). CVIB at 10 mg/kg i.p. efficiently decreased inflammatory parameters better than the physical mixture (carvacrol + ibuprofen 10 mg/kg i.p.). The results suggest that the codrug approach is a good option for drug design and development, creating the possibility of combining NSAIDs with natural products in order to obtain new hybrid drugs may be useful for treatment of inflammatory diseases. Laboratory of Synthesis and Drug Delivery State University of Paraiba Post-Graduation Program in Natural and Synthetic Bioactive Products Federal University of Paraiba Laboratory of Immunomodulation and Novel Therapeutic Approaches Federal University of Pernambuco Laboratory of Neurosciences and Pharmacological Assays (LANEF) University of Sergipe Teaching and Research Management - University Hospital Federal University of Paraiba Department of Antibiotics Center for Biosciences Federal University of Pernambuco Laboratory of Toxicology São Paulo State University (UNESP) School of Pharmaceutical Sciences Health Research and Education Center (NUPADS) Federal University of Mato Grosso Université de Nantes Cibles et Médicaments des Infections et du Cancer IICiMed EA 1155 Laboratory of Toxicology São Paulo State University (UNESP) School of Pharmaceutical Sciences CNPq: 304112/2017-8 CNPq: 306115/2017-4 CNPq: 308590/2017-1

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

2-Allylphenol (2-AP) is a synthetic phenylpropanoid, structurally related to cardanol, thymol, and ortho-eugenol. Phenylpropanoids are described in the literature as being capable of promoting biological activity. Due to the similarity between 2-AP and other bioactive phenylpropanoids, the present research aims at evaluating the antioxidant, antinociceptive, and anti-inflammatory potential of 2-AP in silico,in vitro, andin vivo. At 30 min prior to the start ofin vivopharmacological testing, administration of 2-AP (25, 50, 75, and 100 mg/kg i.p.), morphine (6 mg/kg i.p.), dexamethasone (2 mg/kg s.c.), or vehicle alone was performed. In the acetic acid-induced abdominal writhing tests, pretreatment with 2-AP significantly reduced the number of abdominal writhes, as well as decreased licking times in the glutamate and formalin tests. Investigation of the mechanism of action using the formalin model led to the conclusion that the opioid system does not participate in its activity. However, the adenosinergic system is involved. In the peritonitis tests, 2-AP inhibited leukocyte migration and reduced releases of proinflammatory mediators TNF-αand IL-1β.In vitroantioxidant assays demonstrated that 2-AP presents significant ability to sequester superoxide radicals.In silicodocking studies confirmed interaction between 2-AP and the adenosine A2a receptor through hydrogen bonds with the critical asparagine 253 residues present in the active site. Investigation of 2-AP demonstrated its nociception inhibition and ability to reduce reactive oxygen species. Its interaction with A2a receptors may well be related to proinflammatory cytokines TNF-αand IL-1βreduction activity, corroborating its antinociceptive effect.

Convulsions occur in response to a loss of balance between excitatory and inhibitory neurotransmitters, and the treatment for this condition consists in restore such lost balance. Many anticonvulsant drugs present side effects which may limit their use. This fact has stimulated the search for new sources of treatment from aromatic plants. Many monoterpenes commonly present in essential oils are known because of their anticonvulsant properties. The anticonvulsant effect of α- and β-pinene, two structural isomers, is still little studied. Thus, the present work evaluated the anticonvulsant effect of α- and β-pinene in pentylenetetrazole-induced convulsions model. Initially, the oral LD50 for α- and β-pinene was estimated. Following the oral administration, a mild sedation was observed and no deaths were recorded; the LD50 estimated for both monoterpenes was greater than 2 000 mg/kg, p.o. Further, animals were orally treated with α-pinene (100, 200 and 400 mg/kg), β-pinene (100, 200 and 400 mg/kg) and the equimolar mixture of α- and β-pinene (400 mg/kg) and subjected to the pentylenetetrazole-induced convulsions model. In this model, only the dose of 400 mg/kg of the compounds was able to significantly decrease the seizure intensity. The latency of first convulsion was significantly increased by the mixture of α- and β-pinene (400 mg/kg). In addition, β-pinene and the mixture of the two monoterpenes, both at a dose of 400 mg/kg, significantly increased the time of death of animals. The treatment with β-pinene and the equimolar mixture of the two monoterpenes significantly reduced hippocampal nitrite level and striatal content of dopamine (DA) and norepinephrine (NE). Taken together, the results suggest that α-pinene appears to be devoid of anticonvulsant action. This fact, however, seems to be dependent on the chemical structure of the compound, since pretreatment with the β-pinene increased the time of death pf PTZ-treated mice, which seems to depend on the ability of the compound to reduce nitrite concentration and NE and DA content, during the pentylenetetrazole-induced seizure.

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.

Background: Some research studies have shown that Lippia pedunculosa essential oil (EOLP) has interesting biological activities. However, its low water solubility is the main challenge to achieve its therapeutic potential. In this context, Cyclodextrins (CDs) have been widely used in order to overcome this problem due to your capability to improve the physicochemical properties of drugs. Objective: In this perspective, the main goal of this study was to investigate how the improvement of the physicochemical properties of inclusion complexes (EOLP and β-CD) enhance the antinociceptive effect in mice. Methods: To achieve that, we prepared samples by Physical Mixture (PM), Paste Complexation (PC) and Slurry Complexation (SC) methods, followed by their physicochemical characterization. In addition, it was evaluated if the use of β-CD enhances the antinociceptive effect of EOLP in mice. Results: The analysis showed that rotundifolone (72.02%) was the major compound of EOLP and we found out based on DSC results that β-CD protected it from oxidation. In addition, TG techniques demonstrated that the best inclusion methods were PC and SC, due to their greater weight loss (10.8 and 11.6%, respectively) in the second stage (171-312°C), indicating that more complexed oil was released at the higher temperature than oil free. Other characteristics, such as changes in the typical crystalline form, and reduced particle size were observed by SEM and laser diffraction, respectively. The SC was the most effective complexation method, once the presence of rotundifolone was detected by FTIR. Based on that, SC method was used in all mice tests. In this regard, the number of paw licks was reduced for both compounds (all doses), but EOLP was more effective in reducing the nociceptive behavior. Conclusion: Therefore, CDs seem not to be a good tool to enhance the pharmacological properties of EOs rich in peroxide compounds such as rotundifolone.

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.

Depression is a health problem that compromises the quality of life of the world′s population. It has different levels of severity and a symptomatic profile that affects social life and performance in work activities, as well as a high number of deaths in certain age groups. In the search for new therapeutic options for the treatment of this behavioral disorder, the present review describes studies on antidepressant activity of cinnamic acids, which are natural products found in medicinal plants and foods. The description of the animal models used and the mechanisms of action of these compounds are discussed.

Terpinen-4-ol (4TRP) is a monoterpenoid alcoholic component of essential oils obtained from several aromatic plants. We investigated the psychopharmacological and electrophysiological activities of 4TRP in male Swiss mice and Wistar rats. 4TRP was administered intraperitoneally (i.p.) at doses of 25 to 200 mg/kg and intracerebroventricularly (i.c.v.) at concentrations of 10, 20, and 40 ng/2 μL. For in vitro experiments, 4TRP concentrations were 0.1 mM and 1.0 mM. 4TRP (i.p.) inhibited pentylenetetrazol- (PTZ-) induced seizures, indicating anticonvulsant effects. Electroencephalographic recordings showed that 4TRP (i.c.v.) protected against PTZ-induced seizures, corroborating the behavioural results. To determine whether 4TRP exerts anticonvulsant effects via regulation of GABAergic neurotransmission, we measured convulsions induced by 3-mercapto-propionic acid (3-MP). The obtained results showed involvement of the GABAergic system in the anticonvulsant action exerted by 4TRP, but flumazenil, a selective antagonist of the benzodiazepine site of theGABAAreceptor, did not reverse the anticonvulsant effect, demonstrating that 4TRP does not bind to the benzodiazepine-binding site. Furthermore, 4TRP decreased the sodium current through voltage-dependent sodium channels, and thus its anticonvulsant effect may be related to changes in neuronal excitability because of modulation of these channels.

This study aimed to determine the composition of the essential oil of Mentha x villosa and to evaluate its biological effects in vitro on adult worms of S. mansoni. Rotundifolone (70.96 %), limonene (8.75 %), trans-caryophyllene (1.46 %), and β-pinene (0.81 %) were shown to be the major constituents of this oil. Adult worms of S. mansoni were incubated with different concentrations of the essential oil (1, 10, 100, 250, 500, and 1000 µg/mL) and of its constituents rotundifolone (0.7, 3.54, 7.09, 70.96, 177.4, 354.8, and 700.96 µg/mL), limonene (43.75 µg/mL), trans-caryophyllene (7.3 µg/mL), and β-pinene (4.03 µg/mL). No schistosomicidal activity was identified at the trans-caryophyllene and β-pinene concentrations studied. However, use of the essential oil (10 µg/mL), rotundifolone (7.09 µg/mL), and limonene (43.75 µg/mL) resulted in decreased worm motility continuing until 96 hours of observation. At higher concentrations (100 and 70.96 µg/mL, respectively), both the essential oil and rotundifolone caused mortality among adult worms of S. mansoni. The positive control praziquantel caused the death of all parasites after 24 h of evaluation. The results from this study suggest that the essential oil of Mentha x villosa presents schistosomicidal efficacy.

Immunomodulatory actions exerted by some classes of tryptamines, such as benzoyltryptamine analogues, suggest these molecules as promising candidates to develop new therapies to treat conditions associated to acute and chronic pain and inflammation. N-salicyloyltryptamine (STP) was observed to act as an anticonvulsive agent and exert antinociceptive effects in mouse. In the present work, we performed a screening of cytotoxic, cytoprotective, immunomodulatory, and redox properties of STP in RAW 264.7 macrophages challenged with hydrogen peroxide and LPS. Our results show that STP presents no cytotoxicity in the range of 0.001 to 1 μg/mL, but doses of 50 and 100 μg/mL caused loss of cell viability (IC(50) = 22.75 μg/mL). Similarly, STP at 0.001 to 1 μg/mL did not cause oxidative stress to RAW 264.7 cells, although it did not prevent cell death induced by H(2)O(2) 0.5 mM. At 1 μg/mL, STP reversed some redox and inflammatory parameters induced by LPS. These include thiol (sulfhydryl) oxidation, superoxide dismutase activation, and morphological changes associated to macrophage activation. Besides, STP significantly inhibited LPS-induced TNF-α and IL-1β release, as well as CD40 and TNF-α protein upregulation. Signaling events induced by LPS, such as phosphorylation of ERK 1/2 and IκBα and p65 nuclear translocation (NF-kB activation) were also inhibited by STP. These data indicate that STP is able to modulate inflammatory parameters at doses that do not interfere in cell viability.

α,β-Epoxy-carvone (EC) is a monoterpene found in the essential oils of many species of plants. It can also be obtained by organic synthesis. EC exerts a depressant effect on the central nervous system and is also known to have anticonvulsant, antimicrobial and antioxidant effects. The present study investigated the antinociceptive and anti-inflammatory effects of EC. Intraperitoneal administration of EC at doses of 100, 200 or 300 mg/kg promoted a significant antinociceptive effect, as shown in the acetic acid-induced abdominal writhing test. EC also provoked a reduction in formalin-induced nociception in the first (300 mg/kg) and second phases (200 and 300 mg/kg). In the hot-plate test, an increase in response latency was found at 30 min (at 100, 200 and 300 mg/kg), and at 60 and 120 min (at 300 mg/kg) following administration of EC, an effect that was reversed by naloxone. Intraperitoneal administration of EC (300 mg/kg) inhibited the increased vascular permeability provoked by acetic acid. These findings suggest that EC inhibited the acute inflammatory reaction, with a pronounced peripheral and central antinociceptive effect in mice that is probably associated with activation of the opioidergic system, which appears to play a role in the antinociceptive activity induced by EC.

Terpinen-4-ol is a monoterpenoid alcohol and component of the essential oils of several aromatic plants. Similarly to terpinen-4-ol, other monoterpenoid alcohols have shown anticonvulsant activity in convulsion animal models. The present study aimed to investigate the anticonvulsant activity of terpinen-4-ol. Treatment of mice with terpinen-4-ol ( 200 mg/kg) caused a signifi cant decrease in the spontaneous motor activity at 30, 60 and 120 min after administration. Terpinen-4-ol (100 and 200 mg/kg) produced a significant dosedependent increase in the duration of sleeping in mice. Pretreatment of mice with terpinen-4- ol at doses of 100, 200 and 300 mg/kg significantly increased the latency of pentylenetetrazole -induced convulsions. Terpinen-4-ol (200 and 300 mg/kg) also inhibited the induced seizures of picrotoxin. In another model, maximal electroshock seizure, terpinen-4-ol decreased the tonic hind convulsions percentage at the dose of 300 mg/kg. From the overall results we can conclude that terpinen-4-ol showed a depressant effect on the central nervous system and significant anticonvulsant activity.

The anticonvulsant effect of alpha,beta-epoxy-carvone (EC), a monoterpene monocyclic, was investigated in three animal models. EC at 300 or 400 mg/kg promoted protection of 75% and 87.5%, respectively, against convulsions induced chemically by pentylenetetrazole (PTZ) and it was efficient in prevents the tonic convulsions induced by maximal electroshock (MES) in doses of 200, 300 or 400 mg/kg, resulting in 25%, 25% and 100% of protection, respectively. This monoterpene was also capable to promote an increase of latency for development of convulsions induced by picrotoxin (PIC) at 300 or 400 mg/kg and presented a significant protection against convulsions at doses of 200, 300 or 400 mg/kg, resulting in 12.5%, 12.5% and 100% of protection, respectively. On the other hand, the anticonvulsant effect of EC, was not affected by pretreatment with flumazenil (FLU), a selective antagonist of benzodiazepine site of GABA(A) receptor. Additionally was observed that EC treatment reduced the levels of in vitro lipoperoxidation and decreased (21.2%) the amplitude of compound action potential after 30 min of incubation. The present results clearly indicate the ability of EC to modulate the anticonvulsant and antioxidant effects. However, our data suggests that the action mechanisms are not due a direct activation of the GABA(A) benzodiazepine receptors, but could be associated with the reduction of isolated nerve excitability, possibly involving a voltage-gated Na(+) channels blockade.

Hydroxydihydrocarvone (HC) is a synthetic intermediate obtained from R-(-)-carvone hydration. Due to the chemical and structural similarity between HC and other monoterpenes with psychopharmacological activity, this study was carried out to investigate the possible central antinociceptive effect of intraperitoneally administered HC, and to evaluate its effect on the opioid system in mice. In the tail immersion test, the time of the response to the thermal noxious stimulus was longer in the animals that received HC (200 mg/kg). In the hot plate test, HC (100-200 mg/kg) significantly increased the time mice stayed on the apparatus. In the formalin test, HC was effective in both phases of the test with significant dose-dependent response (50-200 mg/kg), showing central antinociceptive activity. In addition, HC (25-200 mg/kg) did not induce catalepsy in mice. In an attempt to evaluate the mechanism of action of HC, the mice were pretreated with naloxone (5 mg/kg, s.c.). The effect of HC on the formalin and hot plate tests was not blocked by naloxone. Therefore, HC has an antinociceptive effect on the central nervous system without causing catalepsy. These results suggest the nonparticipation of the opioid system in the modulation of pain by HC.

Ortho-eugenol is a much used phenylpropanoid whose ability to reduce pain and inflammation has never been studied. Researching ortho-eugenol's antinociceptive and anti-inflammatory activity, and its possible mechanisms of action is therefore of interest. The administration of vehicle, ortho-eugenol (50, 75 and 100mg/kg i.p.), morphine (6mg/kg, i.p.) or dexamethasone (2mg/kg, s.c.) occurred 30min before the completion of pharmacological tests. Pretreatment with ortho-eugenol did not change motor coordination test results, but reduced the number of writhes and licking times in the writhing test and glutamate test, respectively. The reaction time from thermal stimulus was significantly increased in the hot plate test after administration of ortho-eugenol. Treatment with yohimbine reversed the antinociceptive effect of ortho-eugenol, suggesting involvement of the adrenergic system. In anti-inflammatory tests, ortho-eugenol inhibited acetic acid induced vascular permeability and leukocyte migration, reducing TNF-α and IL-1β by virtue of its suppression of NF-κB and p38 phosphorylated forms in the peritonitis test. From these results, ortho-eugenol antinociceptive effects mediated by the adrenergic system and anti-inflammatory activity through regulation of proinflammatory cytokines and phosphorylation of NF-kB and p38 become evident for the first time.

Geraniol (GER) is a monoterpene alcohol with various biochemical and pharmacological properties present in the essential oil of more than 160 species of herbs (especially the Cymbopogon genus). In this study, we evaluated the antinociceptive activity of GER in behavioural and electrophysiological in vitro experimental models of nociception using male Swiss mice. GER (12.5, 25 or 50 mg/kg i.p. and 50 or 200 mg/kg p.o.) reduced the number of writhes induced by acetic acid. The opioid antagonist naloxone (5 mg/kg s.c.) administered in mice subsequently treated with GER (25 mg/kg i.p.) did not reverse such antinociceptive activity, suggesting a non-opioid pathway for the mechanism of action. GER (12.5, 25 and 50 mg/kg i.p.) reduced paw licking time in the second phase of the formalin test. Also, in the glutamate test, GER when administered 50 mg/kg i.p. reduced paw licking time, probably modulating glutamatergic neurotransmission. GER blocked reversibly components of the compound action potential (CAP) recorded in isolated sciatic nerve in a concentration- and drug exposure time-dependent manner: 1 mM to 120 min. for the first component and 0.6 mM to 90 min. for the second component. The IC50 was calculated for the peak-to-peak amplitude (PPA) at 0.48 ± 0.04 mM. The conduction velocity was also reduced by exposure to GER starting from the concentration of 0.3 mM for both components of the CAP. In conclusion, it is suggested that GER has antinociceptive activity, especially in pain related to inflammation, and in part related to reduced peripheral nerve excitability.

Many terpenes are used therapeutically, and as flavor and fragrance materials. (R)-(-)-Carvone, the main constituent of spearmint oil, and (S)-(+)-carvone, found as major component of caraway and dill seed oils, have several applications and are used in cosmetic, food, and pharmaceutical preparations. In this study, the effect of enantiomers of carvone on the central nervous system (CNS) was evaluated in mice. The LD50 value was 484.2 mg/kg (358.9-653.2) for (S)-(+)-carvone, and 426.6 (389.0-478.6) mg/kg for (R)-(-)-carvone. Both enantiomers caused depressant effects, such as decrease in the response to the touch and ambulation, increase in sedation, palpebral ptosis, and antinociceptive effects. (S)-(+)- and (R)-(-)-carvone caused a significant decrease in ambulation. (R)-(-)-Carvone appeared to be more effective than its corresponding enantiomer at 0.5 and 2.0 h after administration. However, (S)-(+)-carvone was slightly more potent at 1 h. In potentiating pentobarbital sleeping time, (R)-(-)-carvone was more effective than (S)-(+)-carvone at 100 mg/kg, but was less potent at 200 mg/kg compared to the (+)-enantiomer, indicating a sedative action. (S)-(+)-Carvone at the dose of 200 mg/kg increased significantly the latency of convulsions induced by PTZ and PIC, but (R)-(-)-carvone was not effective against these convulsions. These results suggest that (S)-(+)-carvone and (R)-(-)-carvone have depressant effect in the CNS. (S)-(+)-Carvone appears to have anticonvulsant-like activity.

Nerolidol, an acyclic sesquiterpene found as a major constituent of several essential oils, has several pharmacological activities, but its action in pain processes has never been studied. The purpose of our research was to evaluate the antinociceptive and anti-inflammatory activities of nerolidol, as well as possible mechanisms of action, in experimental mouse models of pain. Antinociceptive activity was evaluated using the acetic acid-induced writhing test, the formalin test, and the hot-plate test. The nerolidol-treated group showed lesser acetic acid-induced abdominal contractions than the control group in all of the three doses tested (200, 300, and 400 mg/kg, p.o.). The formalin test doses of 300 and 400 mg/kg p.o. inhibited licking time, in both the first phase and the second phase. In the hot-plate test, nerolidol did not alter latency at any of the observed time points. Motor coordination, evaluated through the rotarod test, was not hindered in animals treated with nerolidol. Regarding the mechanism of action, the antinociceptive activity of nerolidol is related to the GABAergic system, and not to the opioidergic or ATP-sensitive K(+) channels. Treatment with nerolidol reduced carrageenan-induced paw edema. In the model of carrageenan-induced peritonitis, nerolidol decreased the influx of polymorphonuclear cells and also reduced levels of tumor necrosis factor (TNF-α) in peritoneal lavage. Nerolidol reduced production of interleukin 1 beta (IL-1β) in LPS-stimulated, peritoneal macrophages. Thus, these results showed that nerolidol has antinociceptive activity with possible involvement of the GABAergic system, and anti-inflammatory activity, attributed to the suppression of TNF-α and IL-1β proinflammatory cytokines.

The acute treatment of rats and mice with a hydroalcoholic extract from the seeds of Dioclea grandiflora (EHDg) at doses of 250 and 500 mg/kg, by intraperitoneal or oral administration, produced a significant antinociceptive effect in the tail flick and hot plate tests, an effect which was inhibited by naloxone. EHDg given to mice daily for 30 days at a dose of 500 mg/kg, did not cause any observable toxic effect nor any alteration in the pattern of antinociceptive response by the tail immersion test during the course of this treatment. These results suggest that EHDg has a central antinociceptive action devoid of tolerance effect typical of opioid drugs.

Many plant substances are known for their interference with the reproductive system. Mikania glomerata is a plant popularly used to treat respiratory diseases and is reported to have flavonoids and coumarin, which have been shown to have antifertility activity in male dogs and female rats, respectively. This work analyzes the effect of a high dose of M. glomerata extract administered during the spermatogenic cycle of rats. Adult Wistar rats were treated with 1 mL of a M. glomerata extract at a dose level of 3.3 g/kg of body weight for 52 days. Body and organ weights, sperm production, circulating testosterone level and food consumption were evaluated. The results showed that the administration of the M. glomerata extract during the rat spermatogenic cycle did not significantly alter the body and organ weights nor did it interfere with gamete production, serum testosterone level or food intake.

A new tryptamine analogue, N-salicyloyltryptamine (STP), a potential central nervous system (CNS) depressant, was tested in the pentylenetetrazol (PTZ) and maximal electroshock (MES) models of epilepsy in mice. When administered concurrently, STP (100 mg/kg ip) significantly reduced the number of animals that exhibited PTZ-induced seizures and eliminated the extensor reflex of maximal electric-induced seizures test in 50% of the experimental animals. In addition, it showed protection in the PTZ test by diminishing the death rate.

The total alkaloidal fraction of Albizia inopinata leaves (FLA) was investigated for its central nervous system (CNS) effects. FLA (10 mg/kg, i.p.) significantly reduced (45%) the locomotor activity in mice. In addition, it inhibited the conditioned avoidance response behavior and induced ptosis in rats. On the other hand, FLA did not exert significant effect on catalepsy, but potentiated the haloperidol-induced catalepsy. No effect was observed on sleep induced by sodium pentobarbital or apomorphine-induced stereotypes.

An ethanolic extract of the leaves of Cissampelos sympodialis Eichl. (Menispermaceae) was found to potentiate the toxicity of pentylenetetrazol in mice. Similar to imipramine, the extract also reduced the immobility period in the forced swimming test in mice and reversed the degree of ptosis and catalepsy induced by reserpine in rats. These results suggest that the extract possesses antidepressant activity and the reported phosphodiesterase inhibitory activity of the plant may account for the observed antidepressant effect.

Neuropharmacological studies were carried out with reticuline, a benzylisoquinoline alkaloid, isolated from Ocotea duckei Vattimo. It was found that reticuline (50–100 mg/kg i.p.) produced alteration of behaviour pattern, prolongation of pentobarbital-induced sleep, reduction in motor coordination and d -amphetamine-induced hypermotility and suppression of the conditioned avoidance response. These observations suggest that reticuline possesses potent central nervous system depressant action.

The essential oil of Myrtus communis L. (Myrtaceae) and its compounds have been popularly used in numerous health disorders, including insomnia and nervous conditions, but their effects on central nervous system (CNS) have not been explored yet. We evaluated the anxiolytic-like effects and possible action mechanism of (-)-myrtenol (MYR), a monoterpenoid alcohol present in essential oil of M. communis L. Animal models of elevated plus maze (EPM), light-dark transition (LDT), open field and rotarod tests were used in the present study. MYR was administered in male rats. Diazepam was used as the standard drug (positive control) and flumazenil was used to elucidate the possible action mechanism. The results showed that none of the doses of MYR had effect on the resistance time in rotating bar, but caused reduction in the number of falls in rotarod tests when compared with a negative control. Similarly, MYR had no effect on the number of crossings, groomings or rearings in open field tests when compared with a negative control. However, in EPM and LDT tests, MYR significantly increased (p

A series of derivatives analogous to Nb-benzoyltryptamine were synthesized by the Schotten-Bauman procedure. The products obtained were: Nb-4-methoxy-benzoyltryptamine, Nb-2,4-dimethoxy-benzoyltryptamine, Nb-3,4-dimethoxy-benzoyltryptamine, Nb-3,4-methylenedioxy-benzoyltryptamine and Nb-3,4,5-trimethoxy-benzoyltryptamine. They were characterized through the usual spectrometric methods (UV, IR, 1H and 13C NMR) and showed non-selective relaxant activity in guinea-pig ileum pre-contracted with acetylcholine, histamine and KCl.

Farnesol, a sesquiterpene alcohol, has been shown to have antioxidant and anti-inflammatory properties. Recent studies have found that antioxidant compounds may exert a certain protective effect against neurotoxicity. The objective of this study was to evaluate the antinociceptive activity of farnesol (FAR) and its neurotoxic effects on the brains of adult mice. In this study, two mouse models of analgesia were used to evaluate FAR at doses of 50, 100, and 200 mg/kg, injected intraperitoneally (i.p.). In the acetic acid-induced writhing test, a significant decrease was found in the number of contortions in the FAR-treated mice at doses of 50, 100, and 200 mg/kg. FAR was also found to inhibit the licking response in the injected paw at doses of 100 and 200 mg/kg (i.p.) in the first (0-5 min) and second phases (15-30 min) of the formalin test. To evaluate neurotoxic effects, Swiss mice were treated with 0.9% saline (i.p., control group), 0.05 Tween 80 dissolved in 0.9% saline (i.p., vehicle group), and FAR 50, 100, or 200 mg/kg, i.p. Following treatment, all groups were observed for 72 h. In the FAR 200-mg group, 16% of the animals suffered brain injury that affected 12% of the area of the hippocampus. No lesions were found in the hippocampal and striatal regions of the brain in any of the animals treated with the 50 and 100 mg/kg doses of FAR. In conclusion, FAR exerts an antinociceptive effect with no significant neurotoxicity in the brains of adult mice.

(R)-(+)-Pulegone is a monoterpene found in essential oils from plants of the Labiatae family. This compound is a major constituent of Agastache formosanum oil. In this study, the effect of (R)-(+)-pulegone on the central nervous system was evaluated. (R)-(+)-Pulegone caused a significant decrease in ambulation and an increase in pentobarbital-induced sleeping time in mice, indicating a central depressant effect. (+)-Pulegone also significantly increased the latency of convulsions as assessed by the pentylenetetrazole (PTZ) method. The antinociceptive properties of this monoterpene were studied in chemical and thermal models of nociception. Chemical nociception induced in the first and second phase of the subplantar formalin test was significantly inhibited by (R)-(+)-pulegone and was not blocked by naloxone. Thermal nociception was also significantly inhibited while (R)-(+)-pulegone increased the reaction latency of the mice in the hot plate test. These results suggest that (R)-(+)-pulegone is a psychoactive compound and has the profile of an analgesic drug.

α-Terpineol (TPN) is a monoterpenoid alcohol present in the essential oils of several species of the Eucalyptus genus (Myrtaceae).TPN was assessed for its antinociceptive activity in rodents.The antinociceptive effect of TPN was examined using the acetic acid writhing reflex, formalin, glutamate, and capsaicin-induced nociception tests.TPN produced a significant (P 0.01 or P 0.001) analgesic effect by reduction at the early and late phases of paw licking and reduced the writhing reflex in mice (formalin and writhing tests, respectively). In the glutamate test, all doses of TPN produced significant (P 0.01) nociceptive protection. When the capsaicin-induced nociception test was conducted, TPN produced dose-related inhibition of the nociceptive behavior. In addition, the results of a hot plate test showed central analgesic properties for TPN (P 0.01 or P 0.001). Such results were unlikely to be provoked by motor abnormality.Our results suggest that TPN might represent an important tool for management and/or treatment of painful conditions.

Linalool oxide is a monoterpene that is found in some species of aromatic plants. The effects of the inhalation of linalool oxide (0.65%, 1.25%, 2.5% and 5.0% w/w) in the elevated plus-maze and light/dark box tests as animal models of anxiety were investigated in adult male mice and compared with the effects of the reference anxiolytic diazepam (0.5 and 2.0mg/kg), administered intraperitoneally. Additionally, the effects of inhaled linalool oxide were investigated in the rotarod test. Linalool oxide significantly increased the number of visits to the open arms of the elevated plus-maze and the amount of time spent there as well as the total number of entries. In the light/dark box test, inhalation of linalool oxide led to an increase in the time spent by the mice in the brightly-lit chamber and in the number of times the animal crossed from one compartment to another. Performance on the rotarod was unaffected. Thus, inhaled linalool oxide was found to have anxiolytic properties in both animal models, without causing any motor deficit. These results suggest that inhalation of linalool oxide may be a useful means of counteracting anxiety.

Acute treatment with the chloroform fraction ofDioclea virgata(Rich.) Amshoff (CFDv) in mice produced decreased ambulation and sedation in the behavioral pharmacological screening. Doses of 125 and 250 mg/kg CFDv decreased latency of sleep onset in the test of sleeping time potentiation. In the open field, animals treated with CFDv reduced ambulation and rearing (250 mg/kg), as well as defecation (125; 250 mg/kg). Regarding the antinociceptive activity, CFDv (125, 250, 500 mg/kg) increased latency to first writhing and decreased the number of writhings induced by acetic acid. In the formalin test, CFDv (250 mg/kg) decreased paw licking time in the first and second phases indicating antinociceptive activity that can be mediated both peripherally and at the central level. CFDv did not affect motor coordination until 120 minutes after treatment. CFDv shows psychopharmacological effects suggestive of CNS-depressant drugs with promising antinociceptive activity.

Hydroxydihydrocarvone (HC) is a synthetic intermediate obtained by hydration of the natural compound (R)-(-)-carvone. The aim of the present study was to investigate the possible anti-inflammatory activity of orally administered HC. Toxicity, motor coordination, tail immersion test, as well as carrageenan-induced paw edema and myeloperoxidase (MPO) activity or peritonitis were all evaluated in rodents. HC was force-fed to the animals 1 h before the stimulus. The lethal dose 50% (LD50) of orally administered HC was 1259 mg/kg. No changes in motor coordination were recorded in HC-treated mice in the rotarod test. The time of response to the thermoceptive stimulus in the tail immersion test was longer in HC-treated animals (50, 100, and 200 mg/kg) than in the vehicle-treated group. HC also significantly decreased the area under curve of carrageenan-induced rat paw edema at 100 and 200 mg/kg and MPO activity at 200 mg/kg. Carrageenan-induced neutrophil recruitment to the peritoneal cavity was significantly reduced by HC at doses of 100 or 200 mg/kg, but not 50 mg/kg. These findings demonstrate that orally administered HC exerts antinociceptive and anti-inflammatory activities in rats and mice.

The acute treatment of mice with an ethanolic extract from the seed pod ofDioclea grandiflora(EDgP) at doses of 75, 150 and 300 mg/kg by intraperitoneal administration produced a significant antinociceptive effect as displayed by the acetic acid-induced writhing test and the formalin test. The antinociception was observed through the first (neurogenic pain) and second (inflammatory pain) phases in the formalin test. The hot plate test did not show an increase in the antinociceptive latency whereas the motor performance was affected by the administration at 300 mg/kg at the beginning (30 minutes) of the observation period but not at later periods (60 and 120 minutes). These results suggest that EDgP has a central antinociceptive action and a possible anti-inflammatory activity in mice.

We investigated the antinociceptive and nerve excitability effects of theN-salicyloyltryptamine (NST) NST-treated mice exhibited a significant decrease in the number of writhes when 100 and 200 mg/kg (i.p.) were administered (i.p.). This effect was not antagonized by naloxone (1.5 mg/kg, i.p.). NST inhibited the licking response of the injected paw when 100 and 200 mg/kg were administered (i.p.) to mice in the first and second phases of the formalin test. Because the antinociceptive effects could be associated with neuronal excitability inhibition, we performed the single sucrose gap technique and showed that NST (3.57 mM) significantly reduced (29.2%) amplitude of the compound action potential (CAP) suggesting a sodium channel effect induced by NST. Our results demonstrated an antinociceptive activity of the NST that could be, at least in part, associated to the reduction of the action potential amplitude. NST might represent an important tool for pain management.

(−)-Carvone is a monoterpene ketone that is the main active component of Mentha plant species like Mentha spicata. This study aimed to investigate the antinociceptive activity of (−)-carvone using different experimental models of pain and to investigate whether such effects might be involved in the nervous excitability elicited by others monoterpenes. In the acetic acid-induced writhing test, we observed that (−)-carvone-treated mice exhibited a significant decrease in the number of writhes when 100 and 200 mg/kg was administered. It was also demonstrated that (−)-carvone inhibited the licking response of the injected paw when 100 and 200 mg/kg was administered (i.p.) to mice in the first and second phases of the formalin test. Since naloxone (5 mg/kg, s.c.), an opioid antagonist, showed no influence on the antinociceptive action of (−)-carvone (100 mg/kg), this suggested nonparticipation of the opioid system in the modulation of pain induced by (−)-carvone. Such results were unlikely to be provoked by motor abnormality, since (−)-carvone-treated mice did not exhibit any performance alteration on the Rota-rod apparatus. Because the antinociceptive effects could be associated with neuronal excitability inhibition, we performed the single sucrose gap technique and observed that (−)-carvone (10 mM) was able to reduce the excitability of the isolated sciatic nerve through a diminution of the compound action potential amplitude by about 50% from control recordings. We conclude that (−)-carvone has antinociceptive activity associated with decreased peripheral nerve excitability.

Aim of the study Aniba rosaeodora is an aromatic plant which has been used in Brazil folk medicine due to its sedative effect. Therefore, the purpose of the present study was to evaluate the sedative effect of linalool-rich rosewood oil in mice. In addition we sought to investigate the linalool-rich oil effects on the isolated nerve using the single sucrose-gap technique. Materials and methods Sedative effect was determined by measuring the potentiation of the pentobarbital-induced sleeping time. The compound action potential amplitude was evaluated as a way to detect changes in excitability of the isolated nerve. Results The results showed that administration of rosewood oil at the doses of 200 and 300 mg/kg significantly decreased latency and increased the duration of sleeping time. On the other hand, the dose of 100 mg/kg potentiated significantly the pentobarbital action decreasing pentobarbital latency time and increasing pentobarbital sleeping time. In addition, the effect of linalool-rich rosewood oil on the isolated nerve of the rat was also investigated through the single sucrose-gap technique. The amplitude of the action potential decreased almost 100% when it was incubated for 30 min at 100 μg/ml. Conclusions From this study, it is suggested a sedative effect of linalool-rich rosewood oil that could, at least in part, be explained by the reduction in action potential amplitude that provokes a decrease in neuronal excitability.

Rotundifolone, a monoterpene isolated from the essential oil of the leaves of Mentha x villosa, is a constituent of several essential oils and known to have antinociceptive activity. Our recent study demonstrated that the analogues of rotundifolone showed also a significant antinociceptive effect. In the present report, to investigate the correlation between the structure and antinociceptive activity, rotundifolone and its analogues were evaluated in the acetic acid-induced writhing test in mice. All compounds showed to be more antinociceptive than rotundifolone against the pain response induced by acetic acid. Comparing the antinociceptive effect of rotundifolone with limonene oxide and (+)-pulegone, the results demonstrated that the epoxide group contributes as much as the ketone group to the antinociceptive activity of rotundifolone. Similarly, pulegone oxide and carvone epoxide were more antinociceptive than rotundifolone, thereby suggesting that the position of the functional group on the ring also influences the antinociceptive activity. (D)-Carvone produced maximal inhibition of the writhing response and was slightly more active than (+)-carvone. The study showed that by appropriate structural modification it may be possible to develop novel antinociceptive agents.

The central effects of hydroxydihydrocarvone (HC), an analogue of several monoterpenes, were evaluated in animal models. General behavior, locomotor activity, pentobarbital-induced sleeping time, pentylenetetrazol (PTZ)-induced convulsions, and acetic acid-induced writhing were evaluated in mice. The compound caused palpebral ptosis, decreased the response to touch, and increased sedation (general behavioral profile). HC (50-200 mg/kg) caused a significant dose-dependent decrease in the spontaneous motor activity of mice. This compound (100, 200 mg/kg) potentiated the pentobarbital sleeping time, indicating a depressant action. HC also protected the mice against PTZ-induced convulsions at 400 mg/kg. In the acetic acid-induced writhing, the antinociceptive activity of HC was demonstrated with a significant dose-dependent response at a dose range of 25-400 mg/kg. The present results provide evidence that HC has significant psychopharmacologic activity with depressant effects.

Citronellol is one monoterpene alcohol, which is present in the essential oils of various aromatic plant species. This study evaluated the neuroprotective activity of citronellol on pentylenetetrazol- and picrotoxin-induced convulsions and maximal electroshock-induced seizures in mice. Administration of citronellol significantly reduced the number of animals of convulsion induced by pentylenetetrazol and eliminated the extensor reflex of maximal electroshock-induced seizures test in about 80% of the experimental animals. In addition, administration of citronellol showed protection in the pentylenetetrazol and picrotoxin tests by increasing the latency of clonic seizures. We also investigated the effect of citronellol in the rat isolated nerve using the single sucrose-gap technique. We showed that the amplitude of the compound action potential decreased more than 90% when the monoterpene was incubated for 30 min at 6.4 mM and we did not verify any effect on the repolarization of the compound action potential. Taken together, our results demonstrated an anticonvulsant activity of the citronellol that could be, at least in part, explained by the diminution of the action potential amplitude.

Sida cordifolia L. (Malvaceae), known as “malva branca”, is a plant used in the popular medicine for the treatment stomatits, of asthma and nasal congestion. This work researched the acute toxicity of Sida cordifolia and its action on the central nervous system (CNS) because no data in the literature have been found about of pharmacological activity of this plant in the CNS. The hydroalcoholic extract of Sida cordifolia leaves (HESc) was used and the psychopharmacology approach began with the determination of LD 50 , where a low toxicity was observed in mice. Depressive activity on CNS was demonstrated by several alterations in mice's behavior in the pharmacological screening. In the motility test, the HESc showed significant reduction of spontaneous activity at a dose of 1000 mg/kg (i.p.) at 30 and 60 min. The same form the HESc also decreased the ambulation and rearing in open-field test at 30, 60 and 120 min at a dose of 1000 mg/kg (i.p.).

The cardiovascular effects of reticuline, isolated in a pure form from the stem of Ocotea duckei Vattimo, were studied in rats by using a combined in vivo and in vitro approach. In normotensive rats, reticuline (5, 10 and 20 mg/kg, i. v., randomly) injections produced an intense hypotension. This hypotensive response was attenuated after either, L-NAME (20 mg/kg, i. v.), a nitric oxide (NO) synthase inhibitor, or atropine (2 mg/kg, i. v.), a muscarinic receptor antagonist. In isolated rat aortic rings with intact endothelium, reticuline (3 x 10 ( - 6), 3 x 10 ( - 5), 3 x 10 ( - 4), 9 x 10 ( - 4) and 1.5 x 10 ( - 3) M) inhibited in a concentration-dependent manner the contractions induced by phenylephrine (1 microM), KCl (80 mM) and KCl (30 mM), [IC (50) = (0.4 +/- 0.1, 2.4 +/- 0.4 and 3 +/- 0.4) x 10 ( - 4) M, respectively). The effect of reticuline on phenylephrine-induced contractions was attenuated by removal of the vascular endothelium [IC (50) = (2.5 +/- 0.7) x 10 ( - 4) M]. Similar results were obtained after pretreatment of the rings with L-NAME 100 microM [IC (50) = (1.3 +/- 0.1) x 10 ( - 4) M], L-NAME 300 microM [IC (50) = (3 +/- 0.3) x 10 ( - 4) M] or atropine 1 microM [IC (50) = (1.2 +/- 0.2) x 10 ( - 4) M]. On the other hand, the effect of reticuline on phenylephrine-induced contractions was not affected by indomethacin 1 microM [IC (50) = (0.7 +/- 0.3) x 10 ( - 4) M]. Reticuline (3 x 10 ( - 6), 3 x 10 ( - 5), 3 x 10 ( - 4), 9 x 10 ( - 4) and 1.5 x 10 ( - 3) M) antagonized CaCl (2)-induced contractions, and also inhibited the intracellular calcium dependent transient contractions induced by norepinephrine (1 microM), but not those induced by caffeine (20 mM). These results suggest that the hypotensive effect of reticuline is probably due to a peripheral vasodilation in consequence of: 1) muscarinic stimulation and NOS activation in the vascular endothelium, 2) voltage-dependent Ca (2+) channel blockade and/or 3) inhibition of Ca (2+) release from norepinephrine-sensitive intracellular stores.

1. The aim of this work was to study the effects of N-salicyloyltryptamine (STP), a novel anticonvulsant agent, on voltage-gated ion channels in GH3 cells. 2. In this study, we show that STP at 17 microM inhibited up to 59.2+/-10.4% of the Ito and 73.1+/-8.56% of the IKD K+ currents in GH3 cells. Moreover, the inhibitory activity of the drug STP on K+ currents was dose-dependent (IC50=34.6+/-8.14 microM for Ito) and partially reversible after washing off. 3. Repeated stimulation at 1 Hz (STP at 17 microM) led to the total disappearance of Ito current, and an enhancement of IKD. 4. In the cell-attached configuration, application of STP to the bath increased the open probability of large-conductance Ca2+-activated K+ channels. 5. STP at 17 microM inhibited the L-type Ca2+ current by 54.9+/-7.50% without any significant changes in the voltage dependence. 6. STP at 170 microM inhibited the TTX-sensitive Na+ current by 22.1+/-2.41%. At a lower concentration (17 microM), no effect on INa was observed. 7. The pharmacological profile described here might contribute to the neuroprotective effect exerted by this compound in experimental 'in vivo' models.