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.

SUMMARYPurpose: Methylmalonic acidemias are inherited metabolic disorders characterized by methylmalonate (MMA) accumulation and neurologic dysfunction, including seizures. It is known that metabolic crises in affected patients are precipitated by infections. Although growing evidence supports that inflammation facilitates seizures, it is not known whether inflammatory mediators facilitate MMA-induced seizures. Therefore, in this study we investigate the involvement of cyclooxygenase-2 (COX-2) and prostaglandin E 2 (PGE 2 ) in MMA-induced seizures. Methods: Adult male Wistar rats were implanted with electrodes over the parietal cortex for electroencephalography (EEG) recording and a cannula in the right lateral ventricle. Animals were injected with PGE 2 (100 ng/ 2 ll, i.c.v.) or phosphate-buffered saline (PBS) (2 ll, i.c.v.), 15 min before MMA (2.5 lmol/2.5 ll, i.c.v.) or NaCl (2.5 lmol/2.5 ll, i.c.v.). The anticonvulsant effect of celecoxib (0.2; 2 or 20 mg/kg, p.o., 60 min before MMA) on MMA-induced seizures, and whether PGE 2 (10 or 100 ng/ 2 ll, i.c.v.) prevented the anticonvulsant effect of celecoxib (2 mg/kg, p.o.) were also investigated. Key Findings: PGE 2 decreased the latency to MMAinduced jerks and generalized seizures, and increased the amplitude of generalized seizure EEG recordings. The selective COX-2 inhibitor celecoxib at the dose 2 mg/kg, but not at the dose 20 mg/kg, completely prevented MMA-induced seizures. The protective effect of celecoxib (2 mg/kg) against MMA-induced seizures was prevented by PGE 2 . Significance: These results support a role for PGE 2 in the seizures elicited by MMA, which is in agreement with the view that infections may precipitate and exacerbate neurologic dysfunction in patients with MMA acidemic.

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 the GABAA receptor, 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.

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Background: Natural products, such as phenylpropanoids, which are found in essential oils derived from aromatic plants, have been explored during non-clinical psychopharmacology studies, to discover new molecules with relevant pharmacological activities in the central nervous system, especially antidepressant and anxiolytic activities. Major depressive disorder is a highly debilitating psychiatric disorder and is considered to be a disabling public health problem, worldwide, as a primary factor associated with suicide. Current clinically administered antidepressants have late-onset therapeutic actions, are associated with several side effects, and clinical studies have reported that some patients do not respond well to treatment or reach complete remission. Objective: To review important new targets for antidepressant activity and to select phenylpropanoids with antidepressant activity, using Molegro Virtual Docker and Ossis Data Warris, and to verify substances with more promising antidepressant activity. Results and Conclusion: We conducted an in silico molecular modeling study, based on homology, to determine the three-dimensional structure the 5-hydroxytryptamine 2A receptor (5-HT2AR), then performed molecular docking studies and examined the predisposition for cytotoxicity risk among identified molecules. We obtained a model for 5-HT2AR homology, with satisfactory results, indicating the good stereochemical quality of the model. The phenylpropanoid 4- allyl-2,6-dimethoxyphenol showed the lowest binding energy for 5-HT2AR, with results relevant to the L-arginine/nitric oxide (NO)/cGMP pathway, and showed no toxicity within the parameters of mutagenicity, carcinogenicity, reproductive system toxicity, and skin-tissue irritability, when evaluated in silico; therefore, this molecule can be considered promising for the investigation of antidepressant activity.