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1.
J Ethnopharmacol ; 265: 113337, 2021 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-32890709

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: In the Indian system of medicine, Withania somnifera (L.) Dunal, Hemidesmus indicus (R.Br.), Aegle marmelos (L.) Correa, Emblica officinalis Gaertn, Ocimum sanctum (L.) has been mentioned as a remedy for the treatment of anxiety related disorders. Based on their folklore use, a polyherbal combination was derived for the management of anxiety. AIM OF THE STUDY: The present study is aimed to find the best polyherbal combination (PHC), in terms of its pharmacological action, out of two PHC, namely PHC1 and PHC3, prepared based on the previous studies conducted and to carry out the pharmacokinetic (PK) study of the best combination (PHC3). MATERIALS AND METHODS: Pharmacological activities include elevated plus maze model and hole-board test for anti-anxiety screening, gamma amino-butyric acid (GABAA) measurement in brain tissues and superoxide dismutase, lipid peroxidation and reduced glutathione measurement for anti-oxidant screening. RESULTS: PHC3 (100 mg/kg) produced statistically significant (p < 0.05) effect on all the pharmacological outcome measures when compared to alprazolam standard. Therefore, it was chosen for PK study. PK study was carried out using Liquid Chromatography Mass Spectroscopy technique with respect to Withaferin-A. PK parameters such as maximum plasma concentration (Cmax), 16.78 ± 5.32 ng/mL; time of maximum concentration (Tmax), 18 ± 0.12min; half-life (T1/2) 61.20 ± 9.87min; mean residual time (MRT), 7.53 h s; area under the concentration versus time curve (AUC0-1), 1678 ± 34.13 ng/mL; area under the concentration versus time curve from zero to infinity (AUC0-∞), 1705 ± 28.87 ng/mL; total clearance (CL), 290.67 ± 15.89 mL/min and volume of distribution (Vd) 0.054 L were calculated. CONCLUSIONS: The results of the studies revealed that PHC3 possessed significant anxiolytic, anti-oxidant activities and enhanced expression of GABAA mediated inhibition when compared to PHC1. Withaferin-A in PHC3 exhibited a rapid oral absorption in rat plasma. The findings of this study greatly help to provide useful evidence for the development of suitable formulation using PHC3.


Assuntos
Ansiolíticos/farmacologia , Ansiedade/tratamento farmacológico , Extratos Vegetais/farmacologia , Withania/química , Alprazolam/farmacologia , Animais , Ansiolíticos/isolamento & purificação , Ansiolíticos/farmacocinética , Antioxidantes/isolamento & purificação , Antioxidantes/farmacocinética , Antioxidantes/farmacologia , Ansiedade/fisiopatologia , Área Sob a Curva , Modelos Animais de Doenças , Glutationa/metabolismo , Meia-Vida , Índia , Masculino , Extratos Vegetais/química , Extratos Vegetais/farmacocinética , Ratos , Ratos Sprague-Dawley , Distribuição Tecidual , Vitanolídeos/isolamento & purificação , Vitanolídeos/farmacologia
2.
J Ethnopharmacol ; 265: 113452, 2021 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-33069789

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Zhizhu Xiang (ZZX for short) is the root and rhizome of Valeriana jatamansi Jones, which is a Traditional Chinese Medicine (TCM) used to treat various mood disorders for more than 2000 years, especially anxiety. However, there have been few investigations to clarify the compounds in ZZX for the treatment of anxiety. AIM OF THE STUDY: Our previous study has identified five anti-anxiety components, including hesperidin, isochlorogenic acid A, isochlorogenic acid B and isochlorogenic acid C and chlorogenic acid, from extract of ZZX. In order to find the optimal combination and the underlying mechanism of these five components in the treatment of anxiety disorder, researches were designed based on uniform design method and proteomic technology. MATERIALS AND METHODS: The samples with different proportion and content of the five active components were arranged by uniform design method. Then a mathematical model was formulated using partial least square method and stepwise regression analysis. Moreover, the empty bottle stress-induced anxiety rat model was established, and the anti-anxiety effect was recorded by the unconditioned reflex elevated maze test and the open field test. In addition, the isobaric tags for relative and absolute quantitation (iTRAQ) technique, along with the multidimensional liquid chromatography and high-resolution mass spectrometry were applied in proteomic study. At last, the result of proteomic analysis was further confirmed by Western blot. RESULTS: The optimal combination of the components from the extract of ZZX was 1.153 mg/kg hesperidin, 2.197 mg/kg Isochlorogenic acid A, 0.699 mg/kg Isochlorogenic acid B and 1.249 mg/kg Chlorogenic acid. Total 6818 proteins were identified using proteomic analysis and 80 differentially expressed proteins were used for further bioinformatic analysis. These proteins were involved in the neuroactive ligand-receptor interaction, protein digestion and absorption, cholesterol metabolism, Chagas disease, and AGE/RAGE signaling pathway. CONCLUSIONS: The composition and proportion of anti-anxiety components in extract of ZZX was disclosed, and there was an anti-anxiety effect for the combined components of flavonoids and phenolic acids. Through proteomic analysis and Western blot, it was found that the effective components of extract of ZZX can exert synergistic anti-anxiety effects via the regulation of multi-signaling pathways. These findings could provide a preliminary research basis for the development of new low-toxic, efficient, stable and controllable anti-anxiety drugs.


Assuntos
Ansiolíticos/farmacologia , Ansiedade/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Valeriana/química , Animais , Ansiolíticos/química , Ansiolíticos/isolamento & purificação , Cromatografia Líquida , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/isolamento & purificação , Masculino , Espectrometria de Massas , Medicina Tradicional Chinesa , Modelos Teóricos , Raízes de Plantas , Proteômica , Ratos , Ratos Sprague-Dawley , Rizoma , Transdução de Sinais/efeitos dos fármacos
3.
J Ethnopharmacol ; 264: 113285, 2021 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-32827660

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Salvia miltiorrhiza Bunge (Danshen), a traditional Chinese medicine, has demonstrated in modern studies for its pharmacological activities in treatments of CNS disorders like insomnia, dysphoria. However, its application on anxiolytic effect from the ethanol extract of Salvia miltiorrhiza Bunge (SMEtOH) has not yet been reported. MATERIALS AND METHODS: This study investigated the anxiolytic effect of the SMEtOH using the elevated plus-maze test (EPM) and the hole-board test (HBT) with diazepam and buspirone as positive controls. Also, the spontaneous locomotor activity of mice had been investigated in the open field. Further, we have illustrated the anxiolytic mechanisms of SMEtOH with its influencing upon GABAergic and/or serotonergic nervous systems via a method that SMEtOH was co-administered with flumazenil, a benzodiazepine (BZD) antagonist, or a drug (WAY-100635), a selective 5HT1A receptor antagonist. RESULTS: In hole-board test, results presented that SMEtOH increased head-dip counts and duration time. On the other hand, a decrease in spontaneous locomotor activity was observed. In the EPM test, SMEtOH increased the percentage of open-arm entries and the percentage of time spent in open arms. However, when SMEtOH co-administered with flumazenil or WAY-100635, the anxiolytic effect of SMEtOH was significantly counteracted. CONCLUSION: From these results, we can conclude that the anxiolytic mechanism of SMEtOH is exerted through an activation of the BZD and 5HT1A receptors.


Assuntos
Ansiolíticos/farmacologia , Ansiedade/psicologia , Medicamentos de Ervas Chinesas/farmacologia , Aprendizagem em Labirinto/efeitos dos fármacos , Atividade Motora/efeitos dos fármacos , Salvia miltiorrhiza , Animais , Ansiolíticos/isolamento & purificação , Ansiolíticos/uso terapêutico , Ansiedade/tratamento farmacológico , Relação Dose-Resposta a Droga , Medicamentos de Ervas Chinesas/isolamento & purificação , Medicamentos de Ervas Chinesas/uso terapêutico , Masculino , Aprendizagem em Labirinto/fisiologia , Camundongos , Camundongos Endogâmicos ICR , Atividade Motora/fisiologia , Resultado do Tratamento
4.
J Ethnopharmacol ; 265: 113293, 2021 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-32841698

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Kava extract (Piper methysticum) is a phytotherapic mainly used for the treatment of anxiety. Although the reported effects of Kava drinking improving psychotic symptoms of patients when it was introduced to relieve anxiety in aboriginal communities, its effects on models of psychosis-like symptoms are not investigated. AIM OF THE STUDY: To investigate the effects of Kava extract on behavioral changes induced by amphetamine (AMPH) and its possible relation with alterations in monoamine oxidase (MAO) activity. MATERIALS AND METHODS: Mice received vehicle or Kava extract by gavage and, 2 h after vehicle or AMPH intraperitoneally. Twenty-five minutes after AMPH administration, behavioral (elevated plus maze, open field, stereotyped behavior, social interaction and Y maze) and biochemical tests (MAO-A and MAO-B activity in cortex, hippocampus and striatum) were sequentially evaluated. RESULTS: Kava extract exhibited anxiolytic effects in plus maze test, increased the locomotor activity of mice in open field test and decreased MAO-A (in cortex) and MAO-B (in hippocampus) activity of mice. Kava extract prevented the effects of AMPH on stereotyped behavior and, the association between Kava/AMPH increased the number of entries into arms in Y maze test as well as MAO-B activity in striatum. However, Kava extract did not prevent hyperlocomotion induced by AMPH in open field test. The social interaction was not modified by Kava extract and/or AMPH. CONCLUSION: The results showed that Kava extract decreased the stereotyped behavior induced by AMPH at the same dose that promotes anxiolytic effects, which could be useful to minimize the psychotic symptoms in patients.


Assuntos
Anfetamina/farmacologia , Kava/química , Extratos Vegetais/farmacologia , Comportamento Estereotipado/efeitos dos fármacos , Animais , Ansiolíticos/farmacologia , Ansiedade/tratamento farmacológico , Comportamento Animal/efeitos dos fármacos , Locomoção/efeitos dos fármacos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos
5.
J Ethnopharmacol ; 265: 113316, 2021 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-32866569

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Calea zacatechichi is a plant with an extensive popular and ritual use in Mexico. In healthy volunteers, it induces well-being and tranquility senses, and facilitates superficial stages of sleep. However, anxiolytic, and antidepressant-like effects and changes on the sleep-waking stages have not been explored. AIM: To determine anxiolytic and antidepressant-like effects of an aqueous extract of C. zacatechichi (CZ) in rodents and to analyze their effects on hippocampal activity in the rat sleep-waking cycle. MATERIAL AND METHODS: CZ anxiolytic- and antidepressant-like effects were evaluated in several mice and rat behavioral paradigms. CZ effects on temporal distribution of sleep were described, and hippocampus EEG frequency patterns were analyzed during the sleep-waking cycle; absolute and relative powers were analyzed during Rapid Eye Movements (REM) and non-REM sleep stages. CZ chemical analysis was performed by UPLC-ESI-MS. RESULTS: CZ produced specific and robust anxiolytic- and antidepressant-like effects in mice and rats, similar to those of prototypical drugs, at doses ranging from 0.5 to 50 mg/kg. CZ at 100 mg/kg produced visible mild sedative effects in rats, associated with a significant increase in Slow Wave Sleep episodes during a 6 h recording, and enhanced fast frequencies of hippocampus (gamma-band:31-50 Hz) during REM sleep. CONCLUSION: Results could support the well-being and tranquility senses reported by healthy consumers, and to explain the oneiric content during dreams and some improvements in cognitive processes described by consumers. Anxiolytic- and antidepressant-like effects of this species, reported for first time in this study could improve some aspects of mental health.


Assuntos
Ansiolíticos/farmacologia , Antidepressivos/farmacologia , Asteraceae/química , Extratos Vegetais/farmacologia , Animais , Ansiolíticos/administração & dosagem , Ansiolíticos/isolamento & purificação , Antidepressivos/administração & dosagem , Antidepressivos/isolamento & purificação , Comportamento Animal/efeitos dos fármacos , Cognição/efeitos dos fármacos , Relação Dose-Resposta a Droga , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Masculino , México , Camundongos , Extratos Vegetais/administração & dosagem , Ratos , Ratos Wistar , Sono/efeitos dos fármacos , Sono REM/efeitos dos fármacos
6.
Zh Nevrol Psikhiatr Im S S Korsakova ; 120(10): 137-142, 2020.
Artigo em Russo | MEDLINE | ID: mdl-33244970

RESUMO

Treatment resistance is a persistent neurochemical condition characterized by the presence of «hybrid¼ metabolism, which combines both pathological and drug-dependent metabolisms. The difficulties in management and prevention of treatment resistance are associated with a lack of understanding of neurochemical aspects of the development of higher mental functions. The authors suggest that the basic types of species-preserving behavior are associated with the activity of monoaminergic systems while the modulation of their activity is predetermined by local neuronal networks in the rostral parts of the brain, where a variety of co-transmitters play an important role. It is emphasized that the mechanisms of the development of resistance after previous treatment with agonists (antidepressants, anxiolytics) or antagonists (antipsychotics) are different. Depending on drug actions on synaptic transmission, methodological aspects of treatment resistance management by means of «polar therapy¼, «sensitization¼ and combination strategies are considered.


Assuntos
Ansiolíticos , Antipsicóticos , Psiquiatria , Ansiolíticos/farmacologia , Ansiolíticos/uso terapêutico , Antidepressivos , Antipsicóticos/uso terapêutico , Encéfalo , Psicotrópicos/farmacologia , Psicotrópicos/uso terapêutico
7.
Life Sci ; 259: 118271, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32798553

RESUMO

AIMS: Cannabidiolic acid (CBDA) is one of the most abundant phytocannabinoid acids in the Cannabis sativa plant. It has been shown that it is able to exert some therapeutic effects such as antiemetic, anti-inflammatory, anxiolytic or antidepressant, although some of them remain under debate. In the present study we aim to assess the potential behavioural effects of CBDA as well as its modulation of neuroinflammatory markers in the prefrontal cortex (PFC). MAIN METHODS: The effects of acute and repeated CBDA (0.001-1 mg/kg i.p.) treatments were evaluated on cognitive, emotional, motivational and nociceptive behaviours in male CD1 mice. For this, Y-maze and elevated plus maze paradigms, spontaneous locomotor activity, social interaction, hot-plate, formalin and tail suspension tests were used. We also studied the effects of CBDA on the rewarding responses of cocaine in the conditioned place preference (CPP) paradigm. Finally, PFC was dissected after acute and repeated CBDA treatments to evaluate inflammatory markers. KEY FINDINGS: Acute CBDA treatment induced antinociceptive responses in the hot-plate test. A 10-day CBDA treatment reduced despair-like behaviour in the tail suspension test. CBDA did not alter the results of the remaining behavioural tests assayed, including cocaine-induced reward in the CPP. Regarding the biochemical analysis, repeated CBDA treatment diminished the level of peroxisome proliferator-activated receptor gamma (PPAR-γ) and increased that of interleukin-6 (IL-6) protein in PFC. SIGNIFICANCE: These results show that CBDA has limited in vivo effects on the modulation of mice behaviour, supporting the current skepticism regarding its therapeutic potential.


Assuntos
Comportamento Animal/efeitos dos fármacos , Canabinoides/farmacologia , Córtex Pré-Frontal/efeitos dos fármacos , Animais , Ansiolíticos/farmacologia , Antieméticos/farmacologia , Canabinoides/metabolismo , Cannabis/efeitos dos fármacos , Cognição/efeitos dos fármacos , Condicionamento Psicológico/efeitos dos fármacos , Dronabinol/farmacologia , Emoções/efeitos dos fármacos , Cloreto de Lítio/farmacologia , Masculino , Camundongos , Motivação/efeitos dos fármacos , Nociceptores/efeitos dos fármacos
8.
Life Sci ; 261: 118359, 2020 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-32861795

RESUMO

AIMS: The aim of this study is to investigate the anxiolytic activity of perampanel, a non-competitive antagonist of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-type glutamate receptors, which is approved for partial-onset seizures in patients with epilepsy, and its mechanism of action. MAIN METHODS: The anxiolytic activity of perampanel at the doses of 0.25, 0.5, 1, 2, and 4 mg/kg intraperitoneally (i.p.) was investigated in mice using elevated plus-maze, hole-board, and open-field tests. The findings were compared to the anxiolytic activity of gamma-aminobutyric acid type A benzodiazepine (GABAA/BZ) receptor allosteric modulator diazepam (1 mg/kg, i.p.) and AMPA antagonist GYKI-53655 (5 mg/kg, i.p.). The mechanisms of action of perampanel were evaluated by pre-treatment with GABAA/BZ receptor antagonist flumazenil (3 mg/kg, i.p.), serotonin 5-hydroxytryptamine 1A (5-HT1A) antagonist WAY-100635 (1 mg/kg, i.p.), and α2-adrenoreceptor antagonist yohimbine (5 mg/kg, i.p.). KEY FINDINGS: In the elevated plus-maze and open-field tests, perampanel at the dose of 0.5 mg/kg, and in the hole-board test, at the doses of 0.25, 0.5, and 1 mg/kg demonstrated an anxiolytic effect without altering the locomotor activity. The effect of perampanel was comparable to the effect of diazepam. Stimulation of GABAA/BZ and α2-adrenergic receptors contributed to the anxiolytic effect of perampanel, since significant antagonisms were determined in various behavioral parameters by the antagonist pre-treatments. SIGNIFICANCE: AMPA antagonism is believed to provide the determined anxiolytic activity of perampanel. Increased GABAergic tonus induced by AMPA receptor antagonism along with other systems, especially the noradrenergic system, might be involved in the anxiolytic activity.


Assuntos
Ansiolíticos/uso terapêutico , Ansiedade/tratamento farmacológico , Piridonas/uso terapêutico , Animais , Ansiolíticos/farmacologia , Ansiedade/fisiopatologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Atividade Motora/efeitos dos fármacos , Piridonas/farmacologia , Receptores Adrenérgicos alfa 2/metabolismo , Receptores de GABA/metabolismo
9.
Eur J Med Chem ; 200: 112405, 2020 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-32492595

RESUMO

A series of 4-phenyl-6H-imidazo[1,5-a]thieno[3,2-f][1,4]diazepine-7-carboxylate esters were synthesized and tested as central benzodiazepine receptor (CBR) ligands by the ability to displace [3H]flumazenil from rat cortical membranes. All the compounds showed high affinity with IC50 values ranging from 5.19 to 16.22 nM. In particular, compounds 12b (IC50 = 8.66 nM) and 12d (IC50 = 5.19 nM) appeared as the most effective ligands being their affinity values significantly lower than that of diazepam (IC50 = 18.52 nM). Compounds 12a-f were examined in vivo for their pharmacological effects in mice and five potential benzodiazepine (BDZ) actions were thus taken into consideration: anxiolytic, anticonvulsant, anti-amnesic, hypnotic, and locomotor activities. All the new synthesized compounds were able to induce a significant antianxiety effect and, among them, compound 12f protected pentylenetetrazole (PTZ)-induced convulsions in a dose-dependent manner reaching a 40% effect at 30 mg/kg. In addition, all the compounds were able to significantly prevent the memory impairment evoked by scopolamine, while none of them was able to interfere with pentobarbital-evoked sleep and influence motor coordination. Moreover, title compounds did not affect locomotor and exploratory activity at the same time and doses at which the anti-anxiety effect was observed. Finally, molecular docking simulations were carried out in order to assess the binding mode for compounds 12a-f. The obtained results demonstrated that these compounds bind the BDZ binding site in a similar fashion to flumazenil.


Assuntos
Ansiolíticos/síntese química , Benzodiazepinas/química , Desenho de Fármacos , Animais , Ansiolíticos/farmacologia , Anticonvulsivantes , Benzodiazepinas/metabolismo , Sítios de Ligação , Locomoção/efeitos dos fármacos , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/prevenção & controle , Camundongos , Simulação de Acoplamento Molecular , Ratos , Receptores de GABA-A/metabolismo
10.
J Pharmacol Exp Ther ; 374(3): 366-375, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32527792

RESUMO

In humans, alcohol is consumed for its rewarding and anxiolytic effects. The central nucleus of the amygdala (CeA) is considered a neuronal nexus that regulates fear, anxiety, and drug self-administration. Manipulations of the CeA alter ethanol (EtOH) consumption under numerous EtOH self-administration models. The experiments determined whether EtOH is reinforcing/anxiolytic within the CeA, whether selective breeding for high alcohol consumption alters the rewarding properties of EtOH in the CeA, and whether the reinforcing/anxiolytic effects of EtOH in the CeA are mediated by the neuropeptides corticotropin-releasing factor (CRF) and nociceptin. The reinforcing properties of EtOH were determined by having male Wistar and Taconic alcohol-preferring (tP) rats self-administer EtOH directly into the CeA. The expression of anxiety-like behaviors was assessed through multiple behavioral models (social interaction, acoustic startle, and open field). Coadministration of EtOH and a CRF1 antagonist (NBI35965) or nociceptin on self-administration into the CeA and anxiety-like behaviors was determined. EtOH was self-administered directly into the lateral CeA, and tP rats self-administered a lower concentration of EtOH than Wistar rats. EtOH microinjected into the lateral CeA reduced the expression of anxiety-like behaviors, indicating an anxiolytic effect. Coadministration of NBI35965 failed to alter the rewarding/anxiolytic properties of EtOH in the CeA. In contrast, coadministration of the nociceptin enhanced both EtOH reward and anxiolysis in the CeA. Overall, the data indicate that the lateral CeA is a key anatomic location that mediates the rewarding and anxiolytic effects of EtOH, and local nociceptin receptors, but not local CRF1 receptors, are involved in these behaviors. SIGNIFICANCE STATEMENT: Alcohol is consumed for the stimulatory, rewarding, and anxiolytic properties of the drug of abuse. The current data are the first to establish that alcohol is reinforcing and anxiolytic within the lateral central nucleus of the amygdala (CeA) and that the nociceptin system regulates these effects of alcohol within the CeA.


Assuntos
Ansiolíticos/farmacologia , Núcleo Central da Amígdala/efeitos dos fármacos , Etanol/farmacologia , Patrimônio Genético , Peptídeos Opioides/metabolismo , Recompensa , Animais , Comportamento Animal/efeitos dos fármacos , Núcleo Central da Amígdala/fisiologia , Relação Dose-Resposta a Droga , Masculino , Ratos , Ratos Wistar , Comportamento Social
11.
Anticancer Res ; 40(6): 3271-3276, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32487622

RESUMO

BACKGROUND/AIM: This study aimed to determine the anxiolytic effect of a putative glyoxalase 1 inhibitor, piceatannol, as well as its antitumor activities on the stress-induced tumor growth of Lewis lung carcinoma. MATERIALS AND METHODS: The anxiolytic activities of piceatannol (1-30 mg/kg) were assessed using the elevated plus maze (EPM) test. We also evaluated the pharmacological modulation of stress-induced tumor growth; the mice were treated with piceatannol (3 and 30 mg/kg) from the 10th day till the 19th day after administration of the LLC cells. RESULTS: At the low dose (3 mg/kg), piceatannol significantly increased the time spent in the open arms of the EPM test when compared with the vehicle. At higher doses (30 mg/kg), it significantly suppressed the stress-induced enhancement of tumor growth. CONCLUSION: A low dose of piceatannol exerts an anxiolytic effect, and high doses have an antitumor effect.


Assuntos
Ansiolíticos/uso terapêutico , Antineoplásicos/uso terapêutico , Lactoilglutationa Liase/antagonistas & inibidores , Proteínas Tirosina Quinases/uso terapêutico , Estilbenos/uso terapêutico , Animais , Ansiolíticos/farmacologia , Antineoplásicos/farmacologia , Lactoilglutationa Liase/uso terapêutico , Masculino , Camundongos , Proteínas Tirosina Quinases/farmacologia , Estilbenos/farmacologia
12.
Phytother Res ; 34(10): 2721-2729, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32431006

RESUMO

Dammarane sapogenins (DS), an extract derived from ginseng by alkaline hydrolysis of total ginsenosides, possesses high pharmacological activity and higher bioavailability than ginsenosides. The present study was designed to investigate the anxiolytic-like effects of DS in a mouse model of chronic social defeat stress (CSDS). DS (40 and 80 mg/kg) significantly ameliorated social avoidance and anxiety-like behavior in four test models of CSDS, showing increased time in the interaction zone in the social interaction test and in the center of the field in the open field test, an increased percentage of entries and open arm time in the elevated plus maze, and reduced latency to eat in the novelty-suppressed feeding test. Biochemical analyses showed that DS significantly reduced serum corticosterone levels and increased brain concentration of neurotransmitter 5-HT and noradrenaline in CSDS mice. Treatment with DS significantly upregulated BDNF (brain-derived neurotrophic factor), p-CREB/CREB and p-ERK1/2/ERK1/2 protein expression in the hippocampus and prefrontal cortex of CSDS mice. Collectively, these results suggest that DS exerts anxiolytic-like effects in CSDS model mice and the action is mediated, at least in part, by modulating the HPA (hypothalamic-pituitary-adrenal) axis and monoamine neurotransmitter levels, and via ERK/CREB/BDNF signaling pathway.


Assuntos
Ansiolíticos/uso terapêutico , Ansiedade/tratamento farmacológico , Fator Neurotrófico Derivado do Encéfalo/efeitos dos fármacos , Sapogeninas/uso terapêutico , Triterpenos/uso terapêutico , Animais , Ansiolíticos/farmacologia , Modelos Animais de Doenças , Humanos , Masculino , Camundongos , Sapogeninas/farmacologia , Triterpenos/farmacologia , Regulação para Cima
13.
Psychopharmacology (Berl) ; 237(8): 2327-2343, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32399631

RESUMO

RATIONALE: The c-Jun N-terminal kinase (JNK) pathway and neurotrophic factor dysregulation play a critical role in the pathogenesis of neurobehavioral disorders (anxiety and depression). Targeting the JNK pathway and BDNF/VEGF signaling may signify a new avenue for the treatment of neurobehavioral disorders. OBJECTIVES: The present study investigated the effect of matrine (Mat) against anxiety- and depressive-like emotional status in an acute mouse model of burn injury and explores its underlying mechanism. METHODS: In the mouse model of thermal injury, anxiety- and depression-related behaviors were evaluated using the elevated plus-maze test, the light-dark box test, the open-field test, the forced swimming test, and the tail suspension test. The JNK/caspase-3 and BDNF/VEGF proteins were determined by immunohistochemistry. Additionally, proinflammatory cytokine, antioxidant, nitric oxide, and corticosterone levels were also measured. RESULTS: The results showed that treatment with Mat significantly improves anxiety- and depressive-like behaviors. It remarkably reduced the levels of proinflammatory cytokines, malondialdehyde, and nitric oxide in the hippocampus and prefrontal cortex of a mouse brain. It considerably improved burn-induced alteration in the antioxidant status, corticosterone, and BDNF/VEGF. It also inhibited burn-induced apoptotic signaling by downregulating the expression of JNK/caspase-3. Similarly, it prevented DNA damage and histopathological changes in the dentate gyrus of the hippocampus. Furthermore, molecular docking results showed that Mat possess better binding affinity for JNK/caspase-3 and BDNF/VEGF proteins. CONCLUSIONS: These findings provide convincing evidence that Mat improves anxiety- and depressive-like emotional status through modulation of JNK-mediated inflammatory, oxidative stress, apoptotic, and BDNF/VEGF signaling in an acute mouse model of burn injury.


Assuntos
Alcaloides/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Queimaduras/metabolismo , Caspase 3/metabolismo , Sistema de Sinalização das MAP Quinases/fisiologia , Quinolizinas/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Alcaloides/farmacologia , Alcaloides/uso terapêutico , Animais , Ansiolíticos/metabolismo , Ansiolíticos/farmacologia , Ansiolíticos/uso terapêutico , Ansiedade/tratamento farmacológico , Ansiedade/metabolismo , Fator Neurotrófico Derivado do Encéfalo/antagonistas & inibidores , Queimaduras/tratamento farmacológico , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Camundongos , Simulação de Acoplamento Molecular/métodos , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Quinolizinas/farmacologia , Quinolizinas/uso terapêutico , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores
14.
BMC Complement Med Ther ; 20(1): 149, 2020 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-32416725

RESUMO

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.


Assuntos
Ansiolíticos/farmacologia , Benzamidas/farmacologia , Hidrocortisona/urina , Lauraceae , Tiramina/análogos & derivados , Administração Intravenosa , Animais , Comportamento Animal , Biomarcadores/urina , Brasil , Aprendizagem em Labirinto , Análise Multivariada , Ratos , Ratos Wistar , Tiramina/farmacologia
15.
Adv Exp Med Biol ; 1260: 283-296, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32304038

RESUMO

In our society, anxiety and depression are serious health issues that affect a large proportion of the population. Unfortunately, drug therapies are not always effective and can lead to drug abuse, delay of therapeutic effect, dependence, and tolerance. Traditionally, aromatherapy has also been used for anxiety relief and mood improvement. The use of essential oils, in relieving anxiety and depression, does not have the disadvantages associated with currently used drug therapies. In-vivo studies on animal models have verified the anxiolytic effects of these essential oils and the interactions of their major components with central nervous system receptors. Therefore, it seems reasonable to argue that the modulation of glutamate and GABA neurotransmitter systems are likely to be the critical mechanisms responsible for the sedative, anxiolytic, and anticonvulsant proprieties of linalool and essential oils containing linalool in significant proportions. Popular anxiolytic essential oils are generally rich in terpenoid alcohols like linalool, geraniol and citronellol, and the monoterpene limonene (or citral). Therefore, other essential oils or formulations that contain these terpenoids as major components may serve as important aromatherapeutics for relief of anxiety.


Assuntos
Ansiolíticos/uso terapêutico , Ansiedade/tratamento farmacológico , Aromaterapia , Depressão/tratamento farmacológico , Óleos Voláteis/uso terapêutico , Terpenos/uso terapêutico , Animais , Ansiolíticos/química , Ansiolíticos/farmacologia , Anticonvulsivantes/química , Anticonvulsivantes/farmacologia , Anticonvulsivantes/uso terapêutico , Humanos , Hipnóticos e Sedativos/química , Hipnóticos e Sedativos/farmacologia , Hipnóticos e Sedativos/uso terapêutico , Óleos Voláteis/química , Óleos Voláteis/farmacologia , Terpenos/química , Terpenos/farmacologia
16.
J Pharmacol Exp Ther ; 374(1): 200-210, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32265323

RESUMO

Both an agonist and its associated prodrug for metabotropic glutamate2/3 (mGlu2/3) receptors demonstrated anxiolytic efficacy in large, randomized, multicenter, double-blind, placebo-controlled trials studying patients with generalized anxiety disorder (GAD). These mGlu2/3 receptor agonists produced robust preclinical anxiolytic-like effects in rodent models. Several different metabotropic glutamate2 receptor positive allosteric modulators have been found to produce antidepressant-like effects on several preclinical screening paradigms, including differential-reinforcement-of-low-rate 72-second (DRL 72-s) behavior [increased reinforcers, decreased response rate, and cohesive rightward shifts in inter-response time distributions]. Although mGlu2/3 receptor agonists have not been tested formally for therapeutic effects in treating patients with major depressive disorder, these compounds generally fail to exert antidepressant-like effects in preclinical screening paradigms and did not improve depressive symptoms in GAD trials. Thus, the present studies were designed to test the potential antidepressant-like effects of the mGlu2/3 receptor agonist 1S,2S,5R,6S-2-aminobicyclo[3.1.0]hexane-2,6-bicarboxylate monohydrate (LY354740) on the DRL 72-s schedule. LY354740 did not test similarly to clinically validated antidepressant drugs when administered alone or when coadministered with the selective serotonin reuptake inhibitor fluoxetine in rats. Another glutamate-based antidepressant drug, the uncompetitive N-methyl-D-aspartate channel blocker racemic ketamine, exerted antidepressant-like effects when administered at subanesthetic doses in rats. The findings further support the specificity of rat DRL 72-s behavior when screening for anxiolytic versus antidepressant drugs and extend testing of compounds with glutamatergic mechanisms of action. SIGNIFICANCE STATEMENT: The metabotropic glutamate2/3 receptor agonist and clinically validated anxiolytic drug 1S,2S,5R,6S-2-aminobicyclo[3.1.0]hexane-2,6-bicarboxylate monohydrate did not test similar to antidepressant drugs (increased reinforcers, decreased response rate, and cohesive rightward shifts in the inter-response time distribution) when tested on differential-reinforcement-of-low-rate 72-second (DRL 72-s) behavior and also did not enhance the antidepressant-like effects of the serotonin reuptake inhibitor fluoxetine. The uncompetitive N-methyl-D-aspartate receptor antagonist ketamine increased the reinforcement rate, decreased the response rate, and induced a rightward shift in the inter-response time distribution similar to antidepressant drugs; these results confirm the utility of DRL 72-s schedule of reinforcement when testing clinically validated anxiolytic versus antidepressant glutamatergic drugs.


Assuntos
Ansiolíticos/farmacologia , Antidepressivos/farmacologia , Comportamento Animal/efeitos dos fármacos , Ácido Glutâmico/metabolismo , Reforço Psicológico , Animais , Compostos Bicíclicos com Pontes/farmacologia , Cognição/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Função Executiva/efeitos dos fármacos , Comportamento Impulsivo/efeitos dos fármacos , Ketamina/farmacologia , Masculino , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes
17.
Zhongguo Zhong Yao Za Zhi ; 45(1): 14-19, 2020 Jan.
Artigo em Chinês | MEDLINE | ID: mdl-32237406

RESUMO

Anxiety disorders are a common mental illness that seriously endangered physical and mental health of human beings. The etiology of anxiety disorders is closely related to the abnormality of monoamines neurotransmitters, amino acids neurotransmitters and neuropeptides. The long-term use of anti-anxiety chemical drugs has some adverse effects, such as constipation, muscle relaxation, lethargy, tolerance and withdrawal symptoms. However, traditional Chinese medicines have advantages of multi-component, multi-target coordination, with less adverse reactions. Therefore, it is a promising prospect to develop novel anti-anxiety drugs from traditional Chinese medicines and formulas. This article reviewed some traditional Chinese medicines and formulas that can relieve anxiety symptoms. These include traditional Chinese medicines(Panax ginseng, Lycium ruthenium, Morus alba, Bupleurum plus dragon bone oyster soup, Chailong Jieyu Pills, and Naogongtai Formulas) with the effect on monoamine neurotransmitters, such as serotonin, dopamine, and norepinephrine; traditional Chinese medicines(Rehmannia glutinosa, Ziziphus jujuba Mill. var. spinosa, Jielv Anshen Decoction, Baixiangdan Capsules, Antianxietic Compound Prescription Capsules) with the effect on amino acid neurotransmitters, such as glutamic acid, γ-aminobutyrc acid; and traditional Chinese medicines(P. ginseng, Xiaoyao San, Shuyu Ningxin Decoction)with the effect on neuropeptide Y pathway, with the aim to provide theoretical basis for the further development of some novel and more effective anti-anxiety therapeutics from traditional Chinese medicine and formulas.


Assuntos
Ansiolíticos/farmacologia , Medicamentos de Ervas Chinesas/farmacologia , Neurotransmissores , Humanos , Medicina Tradicional Chinesa , Norepinefrina , Serotonina
18.
Sci Rep ; 10(1): 3766, 2020 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-32111885

RESUMO

Th17 cells are critical drivers of autoimmune diseases and immunopathology. There is an unmet need to develop therapies targeting pathogenic Th17 cells for the treatment of autoimmune disorders. Here, we report that anxiolytic FGIN-1-27 inhibits differentiation and pathogenicity of Th17 cells in vitro and in vivo using the experimental autoimmune encephalomyelitis (EAE) model of Th17 cell-driven pathology. Remarkably, we found that the effects of FGIN-1-27 were independent of translocator protein (TSPO), the reported target for this small molecule, and instead were driven by a metabolic switch in Th17 cells that led to the induction of the amino acid starvation response and altered cellular fatty acid composition. Our findings suggest that the small molecule FGIN-1-27 can be re-purposed to relieve autoimmunity by metabolic reprogramming of pathogenic Th17 cells.


Assuntos
Ansiolíticos/farmacologia , Autoimunidade/efeitos dos fármacos , Técnicas de Reprogramação Celular , Encefalomielite Autoimune Experimental , Ácidos Indolacéticos/farmacologia , Células Th17/imunologia , Animais , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/patologia , Encefalomielite Autoimune Experimental/terapia , Camundongos , Camundongos Transgênicos , Receptores de GABA/imunologia , Células Th17/patologia
19.
J Enzyme Inhib Med Chem ; 35(1): 805-814, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32183602

RESUMO

Multi-target drugs can better address the cascade of events involved in oxidative stress and the reduction in cholinergic transmission that occur in Alzheimer's disease than cholinesterase inhibitors alone. We synthesised a series of 3-arylbenzofuranone derivatives and evaluated their antioxidant activity, cholinesterase inhibitory activity, and monoamine oxidase inhibitory activity. 3-Arylbenzofuranone compounds exhibit good antioxidant activity as well as selective acetylcholinesterase inhibitory activity. The IC50 value of anti-acetylcholinesterase inhibition of Compound 20 (0.089 ± 0.01 µM) is similar to the positive drug donepezil (0.059 ± 0.003 µM). According to the experimental results, Compounds 7, 13 show a certain effect in the in vitro evaluation performed and have the potential as drug candidates for the treatment of Alzheimer's disease.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Ansiolíticos/farmacologia , Antioxidantes/farmacologia , Benzofuranos/farmacologia , Inibidores da Colinesterase/farmacologia , Inibidores da Monoaminoxidase/farmacologia , Acetilcolinesterase/metabolismo , Doença de Alzheimer/metabolismo , Animais , Ansiolíticos/síntese química , Ansiolíticos/química , Antioxidantes/síntese química , Antioxidantes/química , Benzofuranos/síntese química , Benzofuranos/química , Compostos de Bifenilo/antagonistas & inibidores , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Relação Dose-Resposta a Droga , Humanos , Modelos Moleculares , Estrutura Molecular , Monoaminoxidase/metabolismo , Inibidores da Monoaminoxidase/síntese química , Inibidores da Monoaminoxidase/química , Picratos/antagonistas & inibidores , Ratos , Ratos Wistar , Relação Estrutura-Atividade
20.
Medicina (Kaunas) ; 56(3)2020 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-32210162

RESUMO

Background and Objectives: Ficus benghalensis (FB) is a commonly found tree in Pakistan and its various parts have folkloric importance in managing neurological ailments. In the present study, methanolic extract of its bark has been tested on an experimental animal model to evaluate memory-enhancing, anxiolytic and antidepressant activities to validate the claimed therapeutic potential. Materials and Methods: Methanolic extract of freshly isolated bark was prepared and subjected to preliminary phytochemical studies and gas chromatography-mass spectrometry (GC-MS) analysis for the presence of phytocomponents. To evaluate its effect on spatial learning, passive-avoidance test-step through (PAT-ST), Y-maze and Morris water maze (MWM) tests were carried out. Open-field (OFT) and elevated plus maze (EPM) tests were employed to explore the anti-anxiety potential of FB while a forced swimming test (FST) was utilized to assess its anti-depressant prospective. FB doses of 100, 200 and 300 mg/kg with positive and negative controls given to Sprague Dawley (SD) rats. Results: phytochemical studies showed the presence of various phytoconstituents including alkaloids, flavonoids, terpenes, phenolics and anthraquinones. The presence of synephrine, aspargine, glucose, fructose and fatty acids was revealed by GC-MS analysis. FB administration led to significant improved memory retention when evaluated through passive avoidance (p < 0.05), Y-maze (p < 0.05) and Morris water maze (p < 0.05) tests in a scopolamine model of amnesic rats. When tested by open field and elevated plus maze tests, FB demonstrated anxiety-resolving characteristics (p < 0.05) as animals dared to stay in open areas more than a control group. Mobility time was increased and immobility time was reduced (p < 0.05-0.01) in rats treated with FB, unveiling the anti-depressant importance of F. benghalensis. Conclusion: methanolic extract of F. benghalensis bark furnished scientific proof behind folkloric claims of the memory improving, anxiety-reducing and depression-resolving characteristics of the plant. These activities might be possible due to interaction of its phytoconstituents with serotonergic, glutamatergic, cholinergic and GABAergic systems in the brain.


Assuntos
Ansiolíticos/farmacologia , Antidepressivos/farmacologia , Comportamento Animal/efeitos dos fármacos , Ficus , Memória/efeitos dos fármacos , Extratos Vegetais/farmacologia , Amnésia/prevenção & controle , Animais , Modelos Animais de Doenças , Feminino , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Modelos Teóricos , Ratos , Ratos Sprague-Dawley , Escopolamina , Aprendizagem Espacial/efeitos dos fármacos
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