RESUMO
Lippia sidoides Cham. (Verbenaceae) is a species often mentioned in traditional medicine due to the medicinal properties attributed to its leaves, which include antibacterial, antifungal, acaricidal and antioxidant. Several of these actions have been scientifically proven, according to reports in the literature; however, little is known about toxicological aspects of this plant. This work included studies to determine the chemical composition and toxicity tests, using several methods aiming to evaluate the safety for use of the aqueous extract of L. sidoides leaves, in addition, the anxiolytic effect on adult zebrafish was investigated, thus contributing to the pharmacological knowledge and traditional medicine concerning the specie under study. The chemical profile was determined by liquid chromatography coupled to mass spectrometry-HPLC/MS with electrospray ionization. Toxicity was evaluated by zebrafish, Drosophila melanogaster, blood cells, and Artemia salina models. 12 compounds belonging to the flavonoid class were identified. In the toxicity assays, the observed results showed low toxicity of the aqueous extract in all tests performed. In the analysis with zebrafish, the highest doses of the extract were anxiolytic, neuromodulating the GABAa receptor. The obtained results support the safe use of the aqueous extract of L. sidoides leaves for the development of new drugs and for the use by populations in traditional medicine.
Assuntos
Ansiolíticos , Lippia , Animais , Ansiolíticos/toxicidade , Peixe-Zebra , Drosophila melanogaster , Folhas de PlantaRESUMO
Benzodiazepines are highly effective in combating anxiety; however, they have considerable adverse effects, so it is important to discover new safe anxiolytic agents. This study was designed to investigate the effect of the natural product 2-hydroxy-3,4,6-trimethoxyacetophenone (HTMCX) on anxiety and seizure behavior in adult zebrafish and its possible mechanisms of action. The acute toxicity of 96 h of HTMCX was analyzed, and the open and light/dark field tests (n = 6 animals/group) were used to assess the anxiety behavior of animals treated with HTMCX. In addition, the mechanisms of action were investigated with antagonists of the GABAA, 5-HT receptors, and molecular anchorage study. Pentylenetetrazole (PTZ) was used to induce seizure by immersion. As a result, acetophenone HTMCX (1, 3 and 10 mg/kg; v.o.) was non-toxic and affected locomotor activity. The higher doses (3 and 10 mg/kg; v.o.) produced signs of anxiolytic action in the light/dark test, and this effect was reversed by the pizotifen (antagonist 5HTR1 and 5HTR2A/2C), having the potential to form a complex with 5HTR1B. However, the anxiolytic effect of HTMCX has not been abolished by flumazenil (antagonist GABAA), cyproheptadine (antagonist 5HTR2A), and granisetron (antagonist 5HTR3A/3B). Therefore, HTMCX demonstrated an anxiolytic effect, suggesting that the 5HTR1 and 5HTR2C receptors may be involved in the pharmacological performance of this acetophenone in the central nervous system.
Assuntos
Acetofenonas/uso terapêutico , Ansiolíticos/uso terapêutico , Ansiedade/tratamento farmacológico , Produtos Biológicos/uso terapêutico , Croton , Neurotransmissores/uso terapêutico , Acetofenonas/farmacologia , Acetofenonas/toxicidade , Animais , Ansiolíticos/farmacologia , Ansiolíticos/toxicidade , Ansiedade/metabolismo , Produtos Biológicos/farmacologia , Produtos Biológicos/toxicidade , Feminino , Masculino , Simulação de Acoplamento Molecular , Neurotransmissores/farmacologia , Neurotransmissores/toxicidade , Pentilenotetrazol , Receptores de Serotonina/metabolismo , Convulsões/induzido quimicamente , Convulsões/tratamento farmacológico , Convulsões/metabolismo , Serotonina/metabolismo , Peixe-ZebraRESUMO
Methylglyoxal (MGO) is a highly reactive dicarbonyl molecule that promotes the formation of advanced glycation end products (AGEs), which are believed to play a key role in a number of pathologies, such as diabetes, Alzheimer's disease, and inflammation. Here, Swiss mice were treated with MGO by intraperitoneal injection to investigate its effects on motor activity, mood, and cognition. Acute MGO treatment heavily decreased locomotor activity in the open field test at higher doses (80-200 mg/kg), an effect not observed at lower doses (10-50 mg/kg). Several alterations were observed 4 h after a single MGO injection (10-50 mg/kg): (a) plasma MGO levels were increased, (b) memory was impaired (object location task), (c) anxiolytic behavior was observed in the open field and marble burying test, and (d) depressive-like behavior was evidenced as evaluated by the tail suspension test. Biochemical alterations in the glutathione and glyoxalase systems were not observed 4 h after MGO treatment. Mice were also treated daily with MGO at 0, 10, 25 and 50 mg/kg for 11 days. From the 5th to the 11th day, several behavioral end points were evaluated, resulting in: (a) absence of motor impairment as evaluated in the open field, horizontal bars and pole test, (b) depressive-like behavior observed in the tail suspension test, and (c) cognitive impairments detected on working, short- and long-term memory when mice were tested in the Y-maze spontaneous alternation, object location and recognition tests, and step-down inhibitory avoidance task. An interesting finding was a marked decrease in dopamine levels in the prefrontal cortex of mice treated with 50 mg/kg MGO for 11 days, along with a ~ 25% decrease in the Glo1 content. The MGO-induced dopamine depletion in the prefrontal cortex may be related to the observed memory deficits and depressive-like behavior, an interesting topic to be further studied as a potentially novel route for MGO toxicity.
Assuntos
Ansiolíticos/toxicidade , Depressão/induzido quimicamente , Dopamina/metabolismo , Transtornos da Memória/induzido quimicamente , Córtex Pré-Frontal/efeitos dos fármacos , Aldeído Pirúvico/toxicidade , Animais , Depressão/metabolismo , Feminino , Lactoilglutationa Liase/metabolismo , Locomoção/efeitos dos fármacos , Memória/efeitos dos fármacos , Transtornos da Memória/metabolismo , Camundongos , Córtex Pré-Frontal/metabolismoRESUMO
The level of acetylcholine, a neurotransmitter essential for processing memory and learning, is lower in the brains of patients with Alzheimer's disease due to the higher concentration of the enzyme acetylcholinesterase. The main compounds used for Alzheimer's treatment are acetylcholinesterase inhibitors. Quercetin coordination complexes with the metal ions Cu+2, Zn+2, Ni+2, Co+2, and Fe+2 were synthesized to investigate their potential use against Alzheimer's disease, by evaluating the inhibition of acetylcholinesterase in vitro and in silico, as well as the antioxidant activity, toxicity, and anxiolytic action in the zebrafish (Danio rerio) model. The organic complexes were characterized by UV-Vis and FT-IR. The spectral information suggested that coordination of metals occurs with the carbonyl group and OH linked to the C-3 carbon of quercetin. The quercetin-Fe (QFe) complex presented the best antioxidant and antiacetylcholinesterase actions, and these results were confirmed by molecular docking. In the toxicity and locomotor evaluation, the quercetin molecules and the synthesized complexes, mainly QCu and QZn derivatives, showed the highest degree of inhibition of the fish's locomotor activity, suggesting a possible anxiolytic action. Then, quercetin complexes with metals, mainly with Fe+2, represent valuable compounds and deserve more investigation as promising agents against Alzheimer's disease.
Assuntos
Ansiolíticos/síntese química , Antioxidantes/síntese química , Inibidores da Colinesterase/síntese química , Simulação por Computador , Complexos de Coordenação/síntese química , Compostos de Ferro/síntese química , Animais , Ansiolíticos/toxicidade , Antioxidantes/toxicidade , Inibidores da Colinesterase/toxicidade , Complexos de Coordenação/toxicidade , Avaliação Pré-Clínica de Medicamentos/métodos , Compostos de Ferro/toxicidade , Locomoção/efeitos dos fármacos , Locomoção/fisiologia , Simulação de Acoplamento Molecular/métodos , Estrutura Secundária de Proteína , Quercetina , Peixe-ZebraRESUMO
AIMS: To explore the antidepressant- and anxiolytic-like effects of an aqueous extract of Turnera diffusa Willd (Turneraceae) and to explore its possible toxic side effects on behavior, target organ function, and spermatic quality. MATERIALS AND METHODS: Acute effects of a T. diffusa aqueous extract were evaluated in adult male mice with the plus-maze, forced swimming and open field tests to identify the possible anxiolytic, antidepressant and stimulant effects of this extract. Effects of T. diffusa aqueous extract were further investigated through two approaches. a) Male and female adult mice receiving a 28-day treatment were evaluated in a neurobehavioral test battery; later, changes in their biochemical parameters and in target organ morphology were analyzed. b) In young adult (16-weeks old) and mature (46-weeks old) males, spermatic quality and testes morphology during a complete spermatogenesis cycle were analyzed after a 35-day treatment. RESULTS: T. diffusa aqueous extract induced remarkable anxiolytic- and antidepressant-like effects without affecting locomotor activity. This extract did not elicit behavioral signs of neural side effects, a sex-dependent reduction in body weight gain was produced without affecting functional parameters or the morphology of target organs. The highest dose improved cellular turnover in the testes of mature mice. CONCLUSION: T. diffusa aqueous extract induced a clear anxiolytic-like effect, and for the first time, we reported an antidepressant effect. Clinical potential or even intake of T. diffusa in the context of traditional medicine can be supported by its efficacy to positively modulate behavior and its safety for a wide range of doses.
Assuntos
Ansiolíticos/farmacologia , Antidepressivos/farmacologia , Comportamento Animal/efeitos dos fármacos , Extratos Vegetais/farmacologia , Turnera/química , Animais , Ansiolíticos/isolamento & purificação , Ansiolíticos/toxicidade , Antidepressivos/isolamento & purificação , Antidepressivos/toxicidade , Relação Dose-Resposta a Droga , Feminino , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Atividade Motora/efeitos dos fármacos , Especificidade de Órgãos , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/toxicidade , Teste de Desempenho do Rota-Rod , Espermatogênese/efeitos dos fármacos , Natação , Testículo/efeitos dos fármacos , Testículo/patologiaRESUMO
We have reported Riparin A as a promising antiparasitic molecule ââagainst Leishmania amazonensis promastigotes. This work evaluated the acute oral toxicity of Riparin A and its anxiolytic effects using in vivo models and computational tools. Mice were submitted to acute oral toxicity tests (Guideline OECD 423). Later, anxiety assays with Riparin A (50, 100 and 200â¯mg/kg: elevated plus maze, light/dark box and marble burying) were performed. Theoretical calculations analyzed interaction of Riparin A with gamma-amino butyric acid (GABA) receptors. Only Riparin A at 2000â¯mg/kg alter body weight, food and water consumption and urine production after 7 and/or 14 days treatment and increased serum triglycerides. There was increase in the time spent in the open arms (TSOA) and number of transitions between compartments (NTC) and decrease in number of hidden balls (NHB) in Riparin A-treated animals at 200â¯mg/kg (Pâ¯<â¯0.05), whose approximate ED50 was 283.1 (156.5-397.1) mg/kg. The functional amide of Riparin A interacted with the GABAA receptor mainly at subunits α2 and ß1 and presented strong interaction with the Asp68 residue, which is part of the pharmacophore group. Riparin A was toxically safe and pharmacologically active for anxiolytic purposes, revealed NOAEL of 200â¯mg/kg and probably interacts with Asp68 residues of benzodiazepine receptors by hydrogen bonds.
Assuntos
Ansiolíticos/farmacologia , Ansiolíticos/toxicidade , Comportamento Animal/efeitos dos fármacos , Benzamidas/farmacologia , Benzamidas/toxicidade , Fenetilaminas/farmacologia , Fenetilaminas/toxicidade , Receptores de GABA-A/metabolismo , Animais , Feminino , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Atividade Motora/efeitos dos fármacos , Nível de Efeito Adverso não Observado , Baço/efeitos dos fármacos , Baço/patologia , Testes de Toxicidade AgudaRESUMO
CONTEXT: Lippia species (Verbenaceae) are widely used in Latin America and Africa as folk medicine for their tranquilizing properties. OBJECTIVE: To evaluate the anxiolytic-like effects and safety of Lippia graveolens Kunth. by exploring its aqueous and organic leaf extracts and identifying the responsible chemical constituents. MATERIAL AND METHODS: Aqueous and organic extracts (hexane, ethyl acetate and methanol) were pharmacologically evaluated at several doses. Chemical constituents were identified using MS, NMR and GC-MS analysis. The isolated compounds (3 mg/kg, i.p.), extracts (1, 3, 10 and 30 mg/kg, i.p.), and the reference drug diazepam (0.1 mg/kg, i.p.) were assessed in CD-1 mice using experimental behavioural models: open-field, cylinder, hole-board, plus-maze and sodium pentobarbital-induced hypnosis, as well as their acute toxicity (LD50). RESULTS: After administration of the extracts and bioactive compounds, a significant anxiolytic-like response from 1 mg/kg, i.p. was observed, resembling the effect of diazepam. Major presence of thymol (33.40%) was observed in the hexane extract; whereas for the first time in this species a p-cymene + thymol mixture (9.78%), naringenin (0.18%) and cirsimaritin (1.16%) were obtained as bioactive constituents of the ethyl acetate crude extract. Acute toxicity was calculated to be LD50 = 1000 mg/kg for the crude hexane extract, lower in comparison to the other extracts analyzed (LD50 > 2000 mg/kg). DISCUSSION AND CONCLUSION: Our results suggest that L. graveolens exerts anxiolytic-like activity involving many kinds of constituents, mainly of the terpenoid and flavonoid nature. These results reinforce the potential use of this species in the therapy of anxiety.
Assuntos
Ansiolíticos/farmacologia , Ansiedade/prevenção & controle , Lippia/química , Compostos Fitoquímicos/farmacologia , Extratos Vegetais/farmacologia , Animais , Ansiolíticos/isolamento & purificação , Ansiolíticos/toxicidade , Ansiedade/psicologia , Comportamento Animal/efeitos dos fármacos , Diazepam/farmacologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Cromatografia Gasosa-Espectrometria de Massas , Dose Letal Mediana , Espectroscopia de Ressonância Magnética , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/toxicidade , Fitoterapia , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/toxicidade , Folhas de Planta/química , Plantas Medicinais , Sono/efeitos dos fármacos , Solventes/químicaRESUMO
A growing body of evidence demonstrates that quinoline compounds have attracted much attention in the field of drug development. Accordingly, 4-phenylselenyl-7-chloroquinoline (4-PSQ) is a new quinoline derivative containing selenium, which showed a potential antioxidant, antinociceptive and anti-inflammatory effect. The present study was undertaken to evaluate the anxiolytic-like properties of 4-PSQ. Mice were orally pretreated with 4-PSQ (5-50 mg/kg) or vehicle, 30 min prior to the elevated plus-maze (EPM), light-dark (LDT) or open field (OFT) tests. A time-response curve was carried out by administration of 4-PSQ (50 mg/kg) at different times before the EPM test. The involvement of glutamate uptake/release and Na+, K+-ATPase activity in the anxiolytic-like effect was investigated in cerebral cortices. In addition, the effectiveness of acute treatment with 4-PSQ was evaluated in a model of kainate (KA)-induced anxiety-related behavior. Finally, acute toxicity of this compound was investigated. 4-PSQ produced an anxiolytic-like action, both in EPM and LDT. In OFT, 4-PSQ did not affect locomotor and exploratory activities. 4-PSQ anxiolytic-like effect started at 0.5 h and remained significant up to 72 h after administration. Treatment with 4-PSQ reduced [3H] glutamate uptake, but the [3H] glutamate release and Na+, K+-ATPase activity were not altered. KA-induced anxiety-related behavior was protected by 4-PSQ pretreatment. Additionally, 4-PSQ exposure did not alter urea levels, aspartate (AST) and alanine aminotrasferase (ALT) activities in plasma. Parameters of oxidative stress in brain and liver of mice were not modified by 4-PSQ. Taken together these data demonstrated that the anxiolytic-like effect caused by 4-PSQ seems to be mediated by involvement of the glutamatergic system.
Assuntos
Ansiolíticos/farmacologia , Ansiedade/tratamento farmacológico , Fármacos Atuantes sobre Aminoácidos Excitatórios/farmacologia , Compostos Organosselênicos/farmacologia , Quinolinas/farmacologia , Administração Oral , Animais , Ansiolíticos/química , Ansiolíticos/toxicidade , Ansiedade/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Fármacos Atuantes sobre Aminoácidos Excitatórios/química , Fármacos Atuantes sobre Aminoácidos Excitatórios/toxicidade , Comportamento Exploratório/efeitos dos fármacos , Comportamento Exploratório/fisiologia , Ácido Glutâmico/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Estrutura Molecular , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Compostos Organosselênicos/química , Compostos Organosselênicos/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Testes Psicológicos , Quinolinas/química , Quinolinas/toxicidade , ATPase Trocadora de Sódio-Potássio/metabolismo , Fatores de Tempo , TrítioRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Agastache mexicana subspecies mexicana (Amm) and xolocotziana (Amx) are used in Mexican traditional medicine to relief cultural affiliation syndromes known as "susto" or "espanto", for "nervous" condition, and as a sleep aid. Despite its intensive use, neuropharmacological studies are scarce, and the chemical composition of the aqueous extracts has not been described. Aims of the study are: (1) To analyze the chemical composition of aqueous extracts from aerial parts of Amm and Amx. (2) To evaluate the anxiolytic-like, sedative, antidepressant-like effects. (3) Analyze the general toxic effects of different doses. MATERIALS AND METHODS: Anxiolytic-like and sedative effects were measured in the avoidance exploratory behavior, burying behavior and the hole-board tests. The antidepressant-like actions were studied in the forced swimming and tail suspension tests. Finally, general activity and motor coordination disturbances were evaluated in the open field, inverted screen and rota-rod tests. The acute toxicity of Amm and Amx was determined by calculating their LD50 (mean lethal dose). The chemical analyses were performed employing chromatographic, photometric and HPLC-ESI-MS techniques. RESULTS: Low doses of Amm and Amx (0.1σ1.0mg/kg) induced anxiolytic-like actions; while higher doses (over 10mg/kg) induced sedation and reduced the locomotor activity, exerting a general inhibition in the central nervous system (CNS). CONCLUSIONS: Results support the use of Amm and Amx in traditional medicine as tranquilizers and sleep inducers. Additionally, this paper contributes to the knowledge of the chemical composition of the aqueous extracts of these plants.
Assuntos
Agastache/química , Ansiolíticos/farmacologia , Hipnóticos e Sedativos/farmacologia , Extratos Vegetais/farmacologia , Animais , Ansiolíticos/isolamento & purificação , Ansiolíticos/toxicidade , Antidepressivos/isolamento & purificação , Antidepressivos/farmacologia , Antidepressivos/toxicidade , Cromatografia Líquida de Alta Pressão , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Hipnóticos e Sedativos/isolamento & purificação , Hipnóticos e Sedativos/toxicidade , Dose Letal Mediana , Masculino , Medicina Tradicional/métodos , México , Camundongos , Atividade Motora/efeitos dos fármacos , Componentes Aéreos da Planta , Extratos Vegetais/administração & dosagem , Extratos Vegetais/toxicidade , Testes de Toxicidade AgudaRESUMO
OBJECTIVES: The aim of this study was to investigate the effects of oral administration of a novel benzodiazepine derivative, JM-20, on the neurological behavior of different rodent models, focusing on the GABAergic effect. We have also investigated the acute toxicity of oral administration of JM-20 in mice. METHODS: Mice or rats received oral administration of JM-20 at 2, 4, 8, and 10 mg/kg to evaluate the sedative/hypnotic, anxiolytic, and anticonvulsant effects, as well as the influence on the stereotyped behavior induced by amphetamine. Diazepam (DZP) was used as a positive control. In addition, the mice received a single oral JM-20 dose of 2000 mg/kg to evaluate the acute toxicity. RESULTS: In a dose-dependent manner, JM-20 (i) increased the number of crossings and decreased the number of rearings in the open-field test; (ii) decreased the aggressive behavior of socially-isolated mice; and (iii) increased the latency period for tonic seizure's onset and the percentage of survival of animals with seizures. Moreover, JM-20 increased the sleeping time induced by barbiturates and the time spent and the number of entries in the open arms of the elevated plus-maze test. In the JM-20 toxicity test, no mortality was observed and only minor signs of toxicity associated with sedation were detected. CONCLUSIONS: These results indicate that JM-20 has an anxiolytic profile similar to DZP and its dihydropyridine moiety did not appear to interfere with the GABAergic activity associated with benzodiazepine. Furthermore, JM-20 did not show significant acute toxic effects in mice.