Avaliação in silico da atividade ansiolítica de compostos do extrato de camomila (Matricaria recutita) nos receptores GABAa humanos / In silico evaluation of the anxiolytic activity of compounds from chamomile (Matricaria recutita) extract in human GABAa receptors

Objetivo: Avaliar a possível atividade ansiolítica de compostos presentes no extrato padronizado de camomila por meio da interação com o receptor GABAa, como também analisar parâmetros farmacocinéticos das moléculas escolhidas por meio de ferramentas computacionais. Método: Simulação da interação proteína-ligante da apigenina, alfa-bisabolol e camazuleno, por meio de docagem molecular com o receptor GABAa, comparadas com diazepam. Por fim, os parâmetros farmacocinéticos dos três compostos foram calculados, usando a ferramenta on line SwissADME. Resultados: Alfa-bisabolol e camazuleno adequaram-se aos parâmetros farmacocinéticos favoráveis, enquanto a apigenina e o diazepam não atenderam ao perfil de ideal de biodisponibilidade. No estudo docking, as energias de ligação obtidas foram de -5-1 (a-bisabolol), -7,0 (camazuleno), -7,5 (diazepam), e -8.3 kcal/mol (apigenina); também foram observadas ligações do tipo hidrofóbicas, de Van der Waals e interações eletrostáticas. Conclusão: Os parâmetros analisados sugerem a atividade ansiolítica das moléculas estudas. Ademais, mais pesquisas in vivo devem ser realizadas a fim de elucidar os resultados e seus mecanismos e possíveis limitações em humanos.

Objective: To evaluate the possible anxiolytic activity of compounds present in standardized chamomile extract through interaction with the GABAa receptor and to analyze pharmacokinetic parameters of the chosen molecules through computational tools. Methods: Simulation of the protein-ligand interaction of apigenin, alpha-bisabolol, and camazulene by molecular docking with the GABAa receptor compared with diazepam. Finally, the pharmacokinetic parameters of the compounds were calculated using the SwissADME online tool. Results: Alpha-bisabolol and camazulene fit the favorable pharmacokinetic parameters, while apigenin and diazepam did not meet the ideal bioavailability profile. In the docking study. The binding energies obtained were -5-1 ( a-bisabolol), -7.0 (camazulene), -7.5 (diazepam), and -8.3 kcal/mol (apigenin). Hydrophobic bonds, Van der Waals and electrostatic interactions were observed. Conclusion: The parameters analyzed suggest an anxiolytic activity of the molecules studied. Also, more in vivo research to elucidate the results and their human and possible resources used in humans

Anxiolytic and antidepressant effects of cannabidiol: a systematic review / Efeitos ansiolíticos e antidepressivos do canabidiol: uma revisão sistemática

Objetctive: Realize a systematic review on articles about cannabidiol (CBD) as an anxiolytic and antidepressant drug. Methodology: A systematic review in PubMed, Science Direct and PsycINFO databases taking into consideration articles published in English and Portuguese from 2008 to 2018 with animal experimentation. Results: Eleven articles with experimental studies on animals were included. All studies exhibited anxiolytic and antidepressant activities after CBD use. Conclusion: It was proven by several experiments the anxiolytic and antidepressant activity of CBD, however there is still a need of more preclinicals and clinicals studies to elucidate its mechanisms.

Objetivo: Realizar uma revisão sistemática de artigos sobre o canabidiol (CBD) como ansiolítico e antidepressivo. Metodos: Revisão sistemática nas bases de dados PubMed, Science Direct e PsycINFO considerando artigos publicados em inglês e português de 2008 a 2018 com experimentação animal. Resultados: Onze artigos com estudos experimentais em animais foram incluídos. Todos os estudos exibiram atividades ansiolíticas e antidepressivas após o uso de CBD. Conclusão: Foi comprovada por diversos experimentos a atividade ansiolítica e antidepressiva do CBD, porém ainda há necessidade de mais estudos pré-clínicos e clínicos para elucidar seus mecanismos.

Standardized extract of Erythrina velutina Willd. attenuates schizophrenia-Like behaviours and oxidative parameters in experimental animal models.

OBJECTIVES: To study the effects of the standardized extract from the leaves of Erythrina velutina in behavioural and oxidative parameters in the ketamine-induced schizophrenia model. METHODS: Mice received ketamine (KET) or saline for 7 days. From 8th to 14th day, the animals received Erythrine (Eryt) (100, 200 or 400 mg/kg) or olanzapine (Olanz), 1 h after KET administration. At 14th day, 30 min after the last administration of KET, the open-field and pre-pulse inhibition (PPI) tests were performed. Then, the animals were sacrificed and the prefrontal cortex (PFC), hippocampus (HC) and striatum (ST) were dissected for the oxidative tests. KEY FINDINGS: Ketamine increased spontaneous locomotor activity and grooming. KET decreased the PPI, which was reversed by combining it with Eryt or olanzapine. KET decreased GSH concentration in PFC and ST this was reversed by Eryt. KET increased MDA concentration in PFC and HC this was reversed by Eryt. Eryt and Olanzapine reduced MDA concentration in ST when compared to KET group. Nitrite concentration was reduced by administration of KET in the PFC. CONCLUSIONS: These results demonstrate that the standardized extract of E. velutina can prevent behavioural symptoms and oxidative stress induced by repeated doses of KET.

Efeito da rutina em modelo de depressão crônico induzido por corticosterona em camundongos / Effect of rutin on a model of chronic corticosterone-induced depression in mice

Introdução: a depressão é uma doença altamente prevalente na população mundial e apesar de não ter sua causa estabelecida, algumas teorias tentam esclarecer sua etiologia. A rutina é um flavonoide pertencente à classe dos flavonóis, que tem propriedades anti-inflamatória e antioxidante. Objetivo: avaliar os efeitos antidepressivos da rutina em um modelo crônico induzido por corticosterona em camundongos. Metodologia: foram utilizados camundongos Swiss fêmeas (25-30g) que receberam corticosterona 20mg/kg ou tween 3% por 21dias. Outros grupos receberam corticosterona por 14 dias e entre 15o ao 21o dia de tratamento, rutina (0,2, 2,0 e 10mg/kg) ou fluoxetina10mg/kg ou diazepam 1mg/Kg. Uma hora após a última administração, os animais passaram pelos testes de campo aberto, labirinto em cruz elevada e nado forçado. Após os testes, os animais foram sacrificados por decapitação e as áreas cerebrais córtex pré-frontal, hipocampo e corpo estriado dissecados. Para análise entre os grupos foi usado o teste "t" de Student e para comparação múltipla dos parâmetros utilizará a Análise de Variância (ANOVA). Resultados: a corticosterona foi capaz de induzir a depressão nos animais. No teste de campo aberto, a rutina 0,2, 2,0 e 10mg/kg reduziram a locomoção. A menor dose da rutina apresentou melhor resposta, aumentando o número de entrada e tempo de permanência no braço aberto no teste de labirinto em cruz elevada. Também reduziu significativamente o tempo de imobilização no teste de nado forçado. Conclusão: a substância apresentou atividades ansiolítica e antidepressiva.

Introduction: Depression is a highly prevalent disease in the world population, and, although its cause is not established, several theories try to clarify its etiology. Rutin is a flavonoid belonging to the subclass of flavonoids, which has anti-inflammatory and antioxidant properties. Objective: to evaluate the antidepressant effects of rutin in a chronic model induced by corticosterone in mice. Methods: Female Swiss mice (25-30g) receiving 20mg / kg corticosterone or 3% tween for 21 days were used. Other groups received corticosterone for 14 days and between 15 and 21 days of treatment, rutin (0.2, 2.0 and 10mg / kg) or fluoxetine 10mg / kg or diazepam 1mg / kg. One hour after the last administration, the animals underwent open field tests, elevated cross labyrinth and forced swimming. After the tests, the animals were sacrificed by decapitation and the cerebral areas, prefrontal cortex, hippocampus and striatum dissected. Student's t-test was used for the analysis between the groups, and Variance Analysis (ANOVA) was used for multiple comparison of the parameters. Results: Corticosterone was able to induce depression in animals. In the open field test, routine 0.2, 2.0 and 10mg / kg reduced the locomotion. The lower dose of rutin presented better response, increasing the number of entry and length of stay in the open arm in the high cross maze test. It also significantly reduced stall time in the forced swim test. Conclusion: the substance presented anxiolytic and antidepressant activities.

The anxiolytic-like effect of 6-styryl-2-pyrone in mice involves GABAergic mechanism of action.

The present work aims to investigate the anxiolytic activity of 6-styryl-2-pyrone (STY), obtained from Aniba panurensis, in behavioral tests and amino acids dosage on male Swiss mice. The animals were treated with STY (1, 10 or 20 mg), diazepam (DZP 1 or 2 mg/kg) or imipramine (IMI 30 mg/kg). Some groups were administered with flumazenil, 30 min before administration of the STYor DZP. The behavioral tests performed were open field, rota rod, elevated plus maze (EPM), hole-board (HB) and tail suspension test (TST). After behavioral tests, these animals were sacrificed and had their prefrontal cortex (PFC), hippocampus (HC) and striatum (ST) dissected for assaying amino acids (aspartate- ASP, glutamate- GLU, glycine- GLY, taurine- TAU and Gamma-aminobutyric acid- GABA). In EPM test, STY or DZP increased the number of entries and the time of permanence in the open arms, but these effects were reverted by flumazenil. In the HB test, STY increased the number of head dips however this effect was blocked by flumazenil. The effects of the STY on amino acid concentration in PFC showed increased GLU, GABA and TAU concentrations. In hippocampus, STY increased the concentrations of all amino acids studied. In striatum, STY administration at lowest dose reduced GLU concentrations, while the highest dosage caused the opposite effect. GLI, TAU and GABA concentrations increased with STY administration at highest doses. In conclusion, this study showed that STY presents an anxiolytic-like effect in behavioral tests that probably is related to GABAergic mechanism of action.

Effects of standard ethanolic extract from Erythrina velutina in acute cerebral ischemia in mice.

The objective of this study was to verify a possible neuroprotective effect of the ethanolic extract of Erythrina velutina (EEEV). Male Swiss mice were submitted to transient cerebral ischemia by occlusion of both carotid arteries for 30 min and treated for 5 days with EEEV (200 or 400 mg/kg) or Memantine (MEM) 10 mg/kg, with initiation of treatment 2 or 24 h after Ischemia. On the 6th day after the induction of ischemia, the animals were submitted to evaluation of locomotor activity and memory and then sacrificed. The brains were dissected for the removal of the prefrontal cortex (PFC), hippocampus (HC) and striatum (ST) for determination of amino acid concentrations. In the step down and Y-maze tests, ischemia caused damage to the animals and treatment with EEEV or MEM reversed this effect. The animals submitted to ischemia also showed memory deficit in the object recognition test, an effect that was reverted by EEEV400 and MEM10. Amino acid dosage showed an increase in excitatory amino acid concentrations in the PFC of the ischemic animals and this effect was reversed by the treatment with EEEV400/24H. Regarding the inhibitory amino acids, ischemia caused an increase of taurine in the PFC while treatment with MEM10/24H or EEEV400/24H reversed this effect. In HC, an increase in excitatory amino acids was also observed in ischemiated animals having treatment with EEEV200/2H or EEEV400/24H reversed this effect. Similar effect was also observed in the same area in relation to the inhibitory amino acids with treatment with MEM10/24H or EEEV400/24H. In the ST, ischemia was also able to cause an increase in excitatory amino acids that was reversed more efficiently by the treatments with MEM10/24H and EEEV200. Also in this area, an increase of taurine and GABA was observed and only the treatment with EEEV200/2H showed a reversion of this effect. In view of these findings, EEEV presents a neuroprotective effect possibly due to its action on amino acid concentrations, and is therefore a potential therapeutic tool in reducing the damage caused by ischemia.

Brain antioxidant effect of mirtazapine and reversal of sedation by its combination with alpha-lipoic acid in a model of depression induced by corticosterone.

BACKGROUND: Depression is accompanied by activated neuro-oxidative and neuro-nitrosative pathways, while targeting these pathways has clinical efficacy in depression. This study aimed to investigate the effects of mirtazapine (MIRT) alone and combined with alpha-lipoic acid (ALA) against corticosterone (CORT) induced behavioral and oxidative alterations. METHODS: Male mice received vehicle or CORT 20mg/kg during 14 days. From the 15th to 21st days they were divided in groups administered: vehicle, MIRT 3mg/kg or the combinations MIRT+ALA100 or MIRT+ALA200. On the 21st day of treatment, the animals were subjected to behavioral tests. Twenty-four hours after the last drug administration hippocampus (HC) and striatum (ST) were dissected for the determination reduced glutathione (GSH), lipid peroxidation (LP) and nitrite levels. RESULTS: CORT induced anxiety- and depressive-like behaviors as observed by increased immobility time in the tail suspension test and decreased sucrose consumption. MIRT or MIRT+ALA are effective in reversing anxiety- and depressive-like behaviors induced by CORT. CORT and MIRT alone prolonged sleeping time and this effect was reversed by MIRT+ALA. CORT significantly increased LP, which was reversed by MIRT or MIRT+ALA. Nitrite levels were increased in CORT-treated animals and reversed by MIRT+ALA200 (HC), MIRT or MIRT+ALA (ST). LIMITATION: A relative small sample size and lack of a washout period between drug administration and behavioral testing. CONCLUSIONS: MIRT or MIRT+ALA reverse CORT-induced anxiety- and depressive-like behaviors probably via their central antioxidant effects. Augmentation of MIRT with ALA may reverse sedation, an important side effect of MIRT. Randomized controlled studies are needed to examine the clinical efficacy of this combination in human depression.

Cocaine-induced status epilepticus and death generate oxidative stress in prefrontal cortex and striatum of mice.

Oxidative stress (OS) has been related to cocaine's actions and also to numerous nervous system pathologies, including seizures. The purpose of this work was to determine the alterations in glutathione (GSH) content, nitrite/nitrate and MDA levels after cocaine-induced toxicity. Male Swiss mice were injected (i.p.) with cocaine 90 mg/kg and observed during 1h. After this cocaine overdose some animals presented status epilepticus (SE) while some died after seizures. These animals were divided in two groups, SE and death. A group with an association of the antioxidant Vitamin E (Vit E, 400mg/kg, i.p.) plus Coc 90 (Vit E plus Coc 90) was undertaken to assess the neuroprotective effect of Vit E. Neurochemical analyses were carried out in prefrontal cortex (PFC) and striatum (ST). GSH levels increased only after cocaine-induced death in both areas studied. Cocaine-induced SE has increased nitrite/nitrate content in PFC and ST, while after death the increase was only in PFC. MDA (the lipid peroxidation marker) was elevated after SE and death in ST and only after death in PFC. Antioxidant treatment significantly reduced the GSH, nitrite/nitrate in ST and MDA levels. Only nitrite/nitrate content in PFC has not been decreased by Vit E pretreatment. The results relate that oxidative stress occurs after cocaine-induced toxicity mainly after death indicating that probably the increase of OS in the animal's brain leads to seizures and death, also showing a protective effect of Vit E in this process. Together with previous results this study contributes to the knowledge of cocaine-induced toxicity and possible in the near future to the use of antioxidants in the prevention of cocaine-induced CNS toxicity.