HIV antiretroviral drug Efavirenz induces anxiety-like and depression-like behavior in rats: evaluation of neurotransmitter alterations in the striatum.

Efavirenz (EFV) is an effective antiretroviral drug with a favorable pharmacokinetic profile and widely used in combination regimens to treat HIV infection. However, there are major concerns about the safety of this drug. Patients treated with EFV often experience neuropsychiatric adverse effects, which frequently lead to switching to alternative EFV-free regimens. The mechanisms involved in the central action of EFV are intrinsically unclear. Thus, this study aimed to investigate the effects of acute and subchronic (2 weeks) EFV administration in a series of behavioral tests for anxiety-like and depression-like behavior in healthy rats. We also evaluated the effect of EFV treatment in striatal concentrations of monoamine neurotransmitters (serotonin, dopamine and noradrenaline) and their metabolites and the amino acid neurotransmitters glutamate and GABA. Our results showed that acute treatment with EFV induced an anxiogenic-like effect, while sub-chronic treatment induced both anxiogenic-like and depressive-like behavior which was dose related.. Additionally, EFV treatment caused marked alterations in the striatal concentrations of monoamines and their metabolites (and turnover rates) and the amino acid neurotransmitters glutamate and GABA. These changes were influenced by treatment duration and dose. These findings add more evidence about the neuropsychiatric adverse effects of EFV and propose potential new mechanisms for the toxic action of this drug in the central nervous system.

Avaliação do potencial anticonvulsivante do extrato padronizado de justicia pectoralis(chambá): estudo de neuroproteção e mecanismo de ação

A epilepsia acomete cerca de 50 milhões de pessoas e 30 % destas apresentam crises refratárias ao tratamento disponível no mercado. O mecanismo da convulsão envolve alteração de neurotransmissores e aminoácidos, estresse oxidativo, excito toxicidade e lesão neuronal. O extrato padronizado de chambá (CH), preparado a partir das partes aéreas da Justicia pectoralis, apresentou em estudos prévios, efeito ansiolítico relacionado à modulação positiva dos receptores GABAA/benzodiazepínicos. Dessa forma, objetivando investigar o potencial anticonvulsivante do chambá, bem como o mecanismo de ação, foram realizados modelos de convulsão induzida por picrotoxina, estricnina, eletrochoque e pilocarpina. Para avaliar a atividade antioxidante através do envolvimento do estresse oxidativo foram mensurados os níveis de peroxidação lipídica, nitrito e a atividade da catalase em hipocampo, corpo estriado e medula (modelo de estricnina) nos modelos de convulsão mencionados acima. Em seguida, foram determinados os níveis de aminoácidos inibitórios (GABA, glicina e taurina) e excitatórios (glutamato e aspartato) no hipocampo após convulsão por pilocarpina e, para verificar a atividade neuroprotetora foram avaliadas a porcentagem de danos neuronais nas áreas CA1 e CA3 do hipocampo após status epilepticusinduzido por pilocarpina. Foram utilizados camundongos Swissfêmeas, tratados por via oral (gavage) e divididos em grupos de acordo com estudo realizado, dentre eles: atividade anticonvulsivante [6 grupos (n=10)...

Epilepsy affects about 50 million people and 30% of these people have refractory seizures to the treatment available. The mechanism of seizure involves alteration in neurotransmitters and amino acids, oxidative stress, excitotoxicity and neuronal injury. The standardized extract of Chamba (CH), prepared from the aerial parts of Justicia pectoralis, presented in previous studies anxiolytic effect related to the upregulation of GABA/benzodiazepine receptors. Thus, with the aim to investigate the anticonvulsant potential of Chamba and its mechanism of action, we performed seizure models induced by picrotoxin, strychnine, electroshock and pilocarpine. To evaluate the antioxidant activity, we measured levels of lipid peroxidation, nitrite and catalase activity in hippocampus, striatum and marrow (strychnine model) in the seizure models mentioned above. Next, we determined the levels of inhibitory amino acid (GABA, glycine, and taurine) and excitatory amino acid (glutamate and aspartate) in the hippocampus after pilocarpine seizure and, to verify neuroprotective activity, we also evaluated the percentage of neuronal damage in the CA1 and CA3 fields of hippocampus after status epilepticus induced by pilocarpine. Swiss female mice were treated orally (gavage) and divided into groups according to the study, among them: anticonvulsant activity [6 groups (n = 10)...

Melatonin: pharmacological aspects and clinical trends.

Melatonin, N-acetyl-5-methoxytryptamine, the major hormone produced by the pineal gland under the influence of the dark/light cycle, has been shown to have a large number of therapeutic possibilities. It has been utilized in several countries for circadian rhythm disorders, sleep disturbances, jet lag, and sleep-wake cycle disturbances in blind people, and shift workers. In our mechanism of act, the G(i) protein-coupled metabotropic melatonin receptors MT1 and MT2 are the primary mediators of the physiological actions of melatonin. This hormone plays an important role in the regulation of physiological and neuroendocrine functions, such as synchronization of seasonal reproductive rhythms and entrainment of circadian cycles. In addition to its chronobiological role, several pharmacological effects of melatonin have been reported in mammals including sedative, antioxidant, anxiolytic, antidepressant, anticonvulsant, and analgesic activities. There is some evidence from clinical trials that melatonin can be helpful in that event. Current trends of pharmacological functions of melatonin pointed out its use in the treatment of neurodegenerative and neoplastic diseases. These effects and uses of melatonin are mentioned but further confirmatory studies are needed in most of them.

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.

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

(-)-Alpha-Bisabolol is an unsaturated, optically active sesquiterpene alcohol obtained by the direct distillation essential oil from plants such as Vanillosmopsis erythropappa and Matricaria chamomilla. (-)-Alpha-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 (-)-alpha-bisabolol on ethanol and indomethacin-induced ulcer models in mice, and further investigate the pharmacological mechanisms involved in this action. The oral administration of (-)-alpha-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 (-)-alpha-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 (-)-alpha-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 (-)-alpha-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.

Anxiolytic-like effect of Carvacrol (5-isopropyl-2-methylphenol) in mice: involvement with GABAergic transmission.

Carvacrol (5-isopropyl-2-methylphenol) is a monoterpenic phenol present in the essencial oil of many plants. It is the major component of the essential oil fraction of oregano and thyme. This work presents the behavioral effects of carvacrol in animal models of elevated plus maze (EPM), open field, Rotarod and barbiturate-induced sleeping time tests in mice. Carvacrol (CVC) was administered orally, in male mice, at single doses of 12.5; 25 and 50 mg/kg while diazepam 1 or 2 mg/kg was used as standard drug and flumazenil (2.5 mg/kg) was used to elucidate the possible anxiolytic mechanism of CVC on the plus maze test. The results showed that CVC, at three doses, had no effect on the spontaneous motor activity in the Rotarod test nor in the number of squares crossed in the open-field test. However, CVC decreased the number of groomings in the open-field test. In the plus maze test, CVC, at three doses significantly increased all the observed parameters in the EPM test and flumazenil was able to reverse the effects of diazepam and CVC. Therefore, CVC did not alter the sleep latency and sleeping time in the barbiturate-induced sleeping time test. These results show that CVC presents anxiolytic effects in the plus maze test which are not influenced by the locomotor activity in the open-field test.