RESUMEN

Epilepsy, frequently comorbid with anxiety, is a prevalent neurological disorder. Available drugs often have side effects that hinder adherence, creating a need for new treatments. Potassium channel activators have emerged as promising candidates for treating both epilepsy and anxiety. This study aimed to evaluate the potential anticonvulsant and anxiolytic effects of pinacidil, an ATP-sensitive potassium channel activator used as antihypertensive, in rats. Our results indicate that pinacidil at 10 mg/kg (i.p.) fully protected animals from seizures induced by pentylenetetrazol (PTZ) and provided 85.7%, 100% and 100% protection against pilocarpine-induced seizures at 2.5, 5 and 10 mg/kg (i.p.), respectively. Although the 2.5 and 5 mg/kg (i.p) doses did not significantly protect the animals from PTZ-induced seizures, they did significantly increase the latency to the first seizure. Pinacidil also demonstrated mild anxiolytic activity, particularly at 10 mg/kg (i.p), evidenced by increased time spent in the open or illuminated areas of the Elevated Plus Maze (EPM) and Light-Dark Box (LDB) and increased exploratory activity in the Open Filed, EPM and LDB. Pinacidil did not affect locomotor performance, supporting its genuine anticonvulsant effects. This study holds significant medical and pharmaceutical value by characterizing pinacidil's anticonvulsant and anxiolytic effects and highlighting its potential for therapeutic repositioning.

Asunto(s)

Ansiolíticos , Anticonvulsivantes , Modelos Animales de Enfermedad , Pentilenotetrazol , Pinacidilo , Convulsiones , Animales , Anticonvulsivantes/farmacología , Anticonvulsivantes/uso terapéutico , Ansiolíticos/farmacología , Ansiolíticos/uso terapéutico , Masculino , Convulsiones/tratamiento farmacológico , Convulsiones/inducido químicamente , Ratones , Ratas , Pinacidilo/farmacología , Reposicionamiento de Medicamentos , Ansiedad/tratamiento farmacológico , Pilocarpina , Conducta Animal/efectos de los fármacos , Ratas Wistar

RESUMEN

In humans, adverse physical and/or psychological traumas in childhood may predispose to developing psychiatric disorders in adulthood, including panic disorder. To model early life adversity in mice, we subjected male and female C57BL/6 J mice to a limited bedding and nesting (LBN) protocol between postnatal days 2-9 and investigated its effect on responsiveness to panicogenic challenges in adulthood. Panic-like escape behaviour was assessed during exposure to a high concentration of CO2 (20%) or in the beetle mania task (BMT), used to model respiratory and non-respiratory-related types of panic respectively. Neonatal exposure to LBN increased panic-like jumping during the CO2 challenge in male but not female mice. In an initial pharmacological validation of the BMT as a panic-inducing paradigm, undirected jumping and horizontal escape behaviours were reduced significantly by the panicolytic alprazolam (0.05 and 0.1mg.kg-1 i.p.) whilst tolerance to the close proximity of the aversive robo-beetle increased. The anxiolytic diazepam (1 mg.kg-1 i.p.) reduced only the number of horizontal escape attempts. In both sexes, previous experience of LBN significantly enhanced the number of horizontal escape episodes, indicating a pro-panic phenotype. Directed escape to access a safe ledge on the wall of the test arena, which was seen only in males, was also reduced significantly following LBN. These findings indicate that early life adversity produced by fragmented and unpredictable maternal care promotes a sex-specific increase in susceptibility to panic-like behaviour in adulthood. Whilst non-respiratory-related panic-like behaviour was enhanced in both sexes, females were resilient to respiratory-related challenges.

Asunto(s)

Animales Recién Nacidos , Ratones Endogámicos C57BL , Animales , Femenino , Masculino , Ratones , Comportamiento de Nidificación/efectos de los fármacos , Comportamiento de Nidificación/fisiología , Pánico/efectos de los fármacos , Pánico/fisiología , Trastorno de Pánico , Caracteres Sexuales , Alprazolam/farmacología , Reacción de Fuga/efectos de los fármacos , Reacción de Fuga/fisiología , Diazepam/farmacología , Ansiolíticos/farmacología , Conducta Animal/efectos de los fármacos , Conducta Animal/fisiología , Dióxido de Carbono/farmacología

RESUMEN

Neoponcirin causes anxiolytic-like effects in mice when administered intraperitoneally but not orally. Neoponcirin is non-water-soluble and insoluble in solvents, and in medium acid, it isomerizes, reducing its bioavailability. To improve the pharmacological properties of neoponcirin, we formed a neoponcirin complex with beta-cyclodextrin (NEO/ßCD), which was characterized by FT-IR, UV-Vis, and NMR, and their solubility profile. We evaluated the antidepressant-like effects of NEO/ßCD acutely administered to mice orally in the behavioral paradigms, the tail suspension (TST) and the forced swimming (FST) tests. We also analyzed the benefits of repeated oral doses of NEO/ßCD on depression- and anxiety-like behaviors induced in mice by chronic unpredictable mild stress (CUMS), using the FST, hole board, and open field tests. We determined the stressed mice's expression of stress-related inflammatory cytokines (IL-1ß, IL-6, and TNFα) and corticosterone. Results showed that a single or chronic oral administration of NEO/ßCD caused a robust antidepressant-like effect without affecting the ambulatory activity. In mice under CUMS, NEO/ßCD also produced anxiolytic-like effects and avoided increased corticosterone and IL-1ß levels. The effects of the NEO/ßCD complex were robust in both the acute and the stress chronic models, improving brain neurochemistry and recovering immune responses previously affected by prolonged stress.

Asunto(s)

Antidepresivos , Depresión , Estrés Psicológico , beta-Ciclodextrinas , Animales , beta-Ciclodextrinas/farmacología , beta-Ciclodextrinas/química , Ratones , Antidepresivos/farmacología , Antidepresivos/uso terapéutico , Masculino , Estrés Psicológico/tratamiento farmacológico , Depresión/tratamiento farmacológico , Conducta Animal/efectos de los fármacos , Citocinas/metabolismo , Modelos Animales de Enfermedad , Ansiedad/tratamiento farmacológico , Ansiolíticos/farmacología , Natación , Administración Oral

RESUMEN

The study focuses on the anxiolytic potential of chalcone (2E,4E)-1-(2-hydroxyphenyl)-5-phenylpenta-2,4-dien-1-one (CHALCNM) in adult zebrafish. Successfully synthesized in 58 % yield, CHALCNM demonstrated no toxicity after 96 h of exposure. In behavioral tests, CHALCNM (40 mg/kg) reduced locomotor activity and promoted less anxious behavior in zebrafish, confirmed by increased permanence in the light zone of the aquarium. Flumazenil reversed its anxiolytic effect, indicating interaction with GABAA receptors. Furthermore, CHALCNM (4 and 20 mg/kg) preserved zebrafish memory in inhibitory avoidance tests. Virtual screening and ADMET profile studies suggest high oral bioavailability, access to the CNS, favored by low topological polarity (TPSA≤75 Å2) and low incidence of hepatotoxicity, standing out as a promising pharmacological agent against the GABAergic system. In molecular coupling, CHALCNM demonstrated superior affinity to diazepam for the GABAA receptor. These results reinforce the therapeutic potential of CHALCNM in the treatment of anxiety, highlighting its possible future clinical application.

Asunto(s)

Ansiolíticos , Conducta Animal , Chalcona , Pez Cebra , Animales , Conducta Animal/efectos de los fármacos , Chalcona/química , Chalcona/farmacología , Chalcona/análogos & derivados , Ansiolíticos/farmacología , Ansiolíticos/química , Ansiolíticos/síntesis química , Receptores de GABA-A/metabolismo , Acroleína/análogos & derivados , Acroleína/química , Acroleína/farmacología , Estructura Molecular , Simulación del Acoplamiento Molecular , Chalconas/farmacología , Chalconas/química , Chalconas/síntesis química , Locomoción/efectos de los fármacos , Relación Estructura-Actividad

RESUMEN

Alamandine is a peptide hormone belonging to the renin-angiotensin system (RAS). It acts through the Mas-related G-protein coupled receptor type D, MrgD, which is expressed in different tissues, including the brain. In the present study, we hypothesize that a lack of alamandine, through MrgD, could cause the anxiety-like behavior in transgenic rats with low brain angiotensinogen [TGR(ASrAOGEN)680]. Adult male transgenic rats exhibited a significant increase in the latency to feeding time in the novelty suppressed feeding test and a decrease in the percentage of time and entries in the open arms in the elevated plus maze. These effects were reversed by intracerebroventricular infusion of alamandine. Pretreatment with D-Pro7-Ang-(1-7), a Mas and MrgD receptor antagonist, prevented the anxiolytic effects induced by this peptide. However, its effects were not altered by the selective Mas receptor antagonist, A779. In conclusion, our data indicates that alamandine, through MrgD, attenuates anxiety-like behavior in male TGR(ASrAOGEN)680, which reinforces the importance of the counter-regulatory RAS axis as promising target for the treatment of neuropsychiatric disorders.

Asunto(s)

Angiotensinógeno , Ansiolíticos , Ansiedad , Encéfalo , Ratas Transgénicas , Receptores Acoplados a Proteínas G , Animales , Masculino , Receptores Acoplados a Proteínas G/metabolismo , Receptores Acoplados a Proteínas G/genética , Ratas , Ansiedad/tratamiento farmacológico , Ansiedad/metabolismo , Ansiolíticos/farmacología , Angiotensinógeno/metabolismo , Angiotensinógeno/genética , Encéfalo/metabolismo , Encéfalo/efectos de los fármacos , Receptores de la Hormona Gastrointestinal/metabolismo , Oligopéptidos/farmacología , Proteínas del Tejido Nervioso

RESUMEN

Alcohol, a widely commercialized psychotropic drug, and the benzodiazepine Flunitrazepam, an anxiolytic widely prescribed for patients with anxiety and insomnia problems, are well known drugs and both act on the central nervous system. The misuse and the association of these two drugs are public health concerns in several countries and could cause momentary, long-lasting and even lethal neurophysiological problems due to the potentiation of their adverse effects in synergy. The present study observed the result of the association of these drugs on electrophysiological responses in the brain, heart, and respiratory rate in Wistar rats. 8 experimental groups were determined: control, one alcohol group (20% at a dose of 1 ml/100 g VO), three Flunitrazepam groups (doses 0.1; 0.2 and 0.3 mg/kg) and three alcohol-Flunitrazepam groups (20% at a dose of 1 ml/100 g VO of alcohol, combined with 0.1; 0.2 and 0.3 mg/kg of Flunitrazepam, respectively). The results showed that there was a more pronounced reduction in alpha and theta wave power in the alcohol-Flunitrazepam groups, a decrease in the power of beta oscillations and greater sedation. There was a progressive decrease in respiratory rate linked to the increase of Flunitrazepam dose in the alcohol-Flunitrazepam associated administration. It was observed alteration in heart rate and Q-T interval in high doses of Flunitrazepam. Therefore, we conclude that the association alcohol-Flunitrazepam presented deepening of depressant synergistic effects according to the increase in the dose of the benzodiazepine, and this could cause alterations in low frequency brain oscillations, breathing, and hemodynamics of the patient.

Asunto(s)

Sinergismo Farmacológico , Electrocardiografía , Etanol , Flunitrazepam , Ratas Wistar , Animales , Masculino , Flunitrazepam/farmacología , Electrocardiografía/efectos de los fármacos , Etanol/farmacología , Electrocorticografía/efectos de los fármacos , Frecuencia Cardíaca/efectos de los fármacos , Depresores del Sistema Nervioso Central/farmacología , Depresores del Sistema Nervioso Central/administración & dosificación , Ratas , Frecuencia Respiratoria/efectos de los fármacos , Ansiolíticos/farmacología , Relación Dosis-Respuesta a Droga , Encéfalo/efectos de los fármacos

RESUMEN

Alcohol use disorder (AUD) is characterized by a set of behavioral, cognitive, nutritional, and physiological phenomena derived from the uncontrolled use of alcoholic beverages. There are cases in which AUD is associated with anxiety disorder, and when untreated, it requires careful pharmacotherapy. Blue Calm® (BC) is a food supplement indicated to aid restorative sleep, which has traces of medicinal plant extracts, as well as myo-inositol, magnesium bisglycinate, taurine, and L-tryptophan as its main chemical constituents. In this context, this study aimed to evaluate the potential of the BC in the treatment alcohol withdrawal-induced anxiety in adult zebrafish (aZF). Initially, BC was submitted to antioxidant activity against 2,2-diphenyl-1-picrylhydrazyl radical. Subsequently, the aZF (n = 6/group) were treated with BC (0.1 or 1 or 10 mg/mL; 20 µL; p.o.), and the sedative effect and acute toxicity (96 h) were evaluated. Then, the anxiolytic-like effect and the possible GABAergic mechanism were analyzed through the Light & Dark Test. Finally, BC action was evaluated for treating alcohol withdrawal-induced anxiety in aZF. Molecular docking was performed to evaluate the interaction of the major chemical constituents of BC with the GABAA receptor. BC showed antioxidant potential, a sedative effect, was not toxic, and all doses of BC had an anxiolytic-like effect and showed potential for the treatment of alcohol withdrawal-induced anxiety in aZF. In addition to the anxiolytic action, the main chemical constituents of BC were confirmed in the molecular docking, thus suggesting that BC is an anxiolytic that modulates the GABAergic system and has pharmacological potential for the treatment of alcohol withdrawal-induced anxiety.

Asunto(s)

Alcoholismo , Ansiolíticos , Síndrome de Abstinencia a Sustancias , Animales , Pez Cebra/fisiología , Ansiolíticos/farmacología , Ansiolíticos/uso terapéutico , Ansiedad/inducido químicamente , Ansiedad/tratamiento farmacológico , Ansiedad/psicología , Alcoholismo/tratamiento farmacológico , Simulación del Acoplamiento Molecular , Síndrome de Abstinencia a Sustancias/tratamiento farmacológico , Receptores de GABA-A , Antioxidantes/farmacología , Antioxidantes/uso terapéutico , Trastornos de Ansiedad/tratamiento farmacológico , Suplementos Dietéticos , Hipnóticos y Sedantes

RESUMEN

Griffinia gardneriana Ravenna, Griffinia liboniana Morren and Griffinia nocturna Ravenna (Amarillydaceae) are bulbous plants found in tropical regions of Brazil. Our work aimed to determine the alkaloid profiles of Griffinia spp. and evaluate their anxiolytic potential through in vivo and in silico assays. The plants grown in greenhouses were dried and their ground bulbs were subjected to liquid-liquid partitions, resulting in alkaloid fractions that were analyzed by gas chromatography coupled to mass spectrometry (GC-MS). Anxiolytic activity was evaluated in zebrafish (Danio rerio) through intraperitoneal injection at doses of 40, 100 and 200 mg/kg in light-dark box test. GC-MS analyses revealed 23 alkaloids belonging to different skeleton types: lycorine, homolychorine, galanthamine, crinine, haemanthamine, montanine and narcisclasine. The chemical profiles were relatively similar, presenting 8 alkaloids common to the three species. The major component for G. gardneriana and G. liboniana was lycorine, while G. nocturna consisted mainly of anhydrolycorine. All three alkaloid fractions demonstrated anxiolytic effect. Furthermore, pre-treatment with diazepam and pizotifen drugs was able to reverse the anxiolytic action, indicating involving the GABAergic and serotonergic receptors. Molecular docking showed that the compounds vittatine, lycorine and 11,12-dehydro-2-methoxyassoanine had high affinity with both receptors, suggesting them to be responsible for the anxiolytic effect.

Asunto(s)

Alcaloides , Alcaloides de Amaryllidaceae , Amaryllidaceae , Ansiolíticos , Fenantridinas , Animales , Amaryllidaceae/química , Pez Cebra , Ansiolíticos/farmacología , Simulación del Acoplamiento Molecular , Cromatografía de Gases y Espectrometría de Masas/métodos , Alcaloides de Amaryllidaceae/farmacología , Alcaloides de Amaryllidaceae/química , Alcaloides/farmacología , Alcaloides/química , Extractos Vegetales/farmacología , Extractos Vegetales/química

RESUMEN

Neuroimaging data in humans and neurobiological studies in rodents have suggested an involvement of the insular cortex (IC) in anxiety manifestations. However, the local neurochemical mechanisms involved are still poorly understood. Corticotropin-releasing factor (CRF) neurotransmission has been described as a prominent neurochemical mechanism involved in the expression of anxiety-like behaviors, but the brain sites related are poorly understood. Additionally, several findings indicate that control of physiological and behavioral responses by the IC occurs in a site-specific manner along its rostrocaudal axis. Thus, this study is aimed at evaluating the effect of CRF receptor agonism and antagonism within the anterior and posterior subregions of the IC in controlling anxiety-related behaviors in the elevated plus maze (EPM). For this, independent groups (six groups) of animals received bilateral microinjections of vehicle, the selective CRF1 receptor antagonist CP376395, or CRF into either the anterior or posterior subregions of the IC. Ten minutes later, the behavior in the EPM was evaluated for five minutes. Treatment of the anterior IC with CP376395, but not with CRF, increased the time and number of entries into the open arms of the EPM. CRF, but not the CRF1 receptor antagonist, microinjected into the posterior IC also increased exploration of the EPM open arms. Taken together, these data indicate that CRFergic neurotransmission in the anterior IC is involved in the expression of anxiety-related behaviors in the EPM. This neurochemical mechanism does not seem to be activated within the posterior IC during exposure to the EPM, but the effects caused by CRF microinjection indicate that activation of CRF receptors in this IC subregion might evoke anxiolytic-like effects.

Asunto(s)

Aminopiridinas , Ansiolíticos , Receptores de Hormona Liberadora de Corticotropina , Humanos , Ratas , Animales , Receptores de Hormona Liberadora de Corticotropina/metabolismo , Hormona Liberadora de Corticotropina/farmacología , Hormona Liberadora de Corticotropina/metabolismo , Prueba de Laberinto Elevado , Corteza Insular , Ansiedad/tratamiento farmacológico , Ansiedad/metabolismo , Ansiolíticos/farmacología

RESUMEN

Perimenopause is a critical period, with severe cycle irregularity and lower estrogen secretion altering redox state biomarkers, leading to behavioral changes. The estrogen hormonal therapy (EHT) being commonly used to alleviate climacteric effects. Therefore, the aim of this study was to analyze anxiolytic profile, recognition memory (short and long term), ambulation, redox status, cell synaptic activity in locus coeruleus and hippocampus of Wistar rats in the periestropause after EHT. Forty rats participated in the study; 20 were treated with corn oil (group 21Mo/Veh; corn oil/0.2 mL/sc; 2x/week) and 20 were submitted to EHT (group 21Mo/E2; 17ß-estradiol/15 µg/Kg/sc; 2x/week) for 120 days. Open field, elevated plus maze, object recognition (RO), and footprint tests were performed immediately before and at the end of the treatment period. From the decapitated brains, isolated hippocampus were destined for biochemical analysis, in turn, perfused brains were destined for histological analysis. The 21Mo/E2 group had a significantly greater total time in the central region and a significantly greater number of entries into the open arms compared to the 21Mo/Veh group, as in crossing, rearing and grooming behaviors, evidencing an anxiolytic profile. In the RO test, the 21Mo/Veh group decreased long-term memory, and the 21Mo/E2 group maintained the same index as at 17 months of age, in addition to a better balance of the hippocampal redox state, prevention of neuronal cell loss and better gait. Based on the results, it appears that exogenous E2 supplementation during periestropause may help preserve neurological functions and potentially prevent neuropsychological and neurodegenerative disorders.

Asunto(s)

Ansiolíticos , Ratas , Femenino , Animales , Humanos , Ansiolíticos/farmacología , Aceite de Maíz/farmacología , Ratas Wistar , Estrógenos/farmacología , Estradiol/farmacología , Cognición , Hipocampo , Ovariectomía

RESUMEN

BACKGROUND: Anxiety disorders represent the complex interaction between biological, psychological, temperamental, and environmental factors; drugs available to treat anxiety such as benzodiazepines (BZDs) are associated with several unwanted side effects. Although there are useful treatments, there is still a need for more effective anxiolytics with better safety profiles than BZDs. Chalcones or 1,3-diphenyl-2-proper-1-ones can be an alternative since this class of compounds has shown therapeutic potential mainly due to interactions with GABAA receptors and serotonergic system. OBJECTIVES: This study evaluated the anxiolytic potential of chalcone (E)-3-(4-(dimethylamino)phenyl)-1-(2-hydroxyphenyl)prop-2-en-1-one (C2OHPDA) in adult zebrafish (Danio rerio) (ZFa). METHODS: Each animal (n = 6/group) was treated intraperitoneally (i.p.; 20 µL) with the chalcone (4, 20, and 40 mg/kg) and with the vehicle (DMSO 3%; 20 µL), being submitted to the tests of locomotor activity and 96-h acute toxicity. The light/dark test was also performed, and the serotonergic mechanism (5-HT) was evaluated through the antagonists of the 5-HTR1 , 5-HTR2A/2C , and 5-HTR3A/3B receptors. It was investigated the prediction of the chalcone's position and preferential orientation concerning its receptor, as well as the pharmacokinetic parameters (ADMET) involved in the process after administration. RESULTS: As a result, C2OHPDA was not toxic and reduced the locomotor activity of ZFa. Furthermore, chalcone demonstrated an anxiolytic effect on the central nervous system (CNS), mediated by the serotonergic system, with action on 5-HT2A and 5-HTR3A/3B receptors. The interaction of C2OHPDA with 5-HT2A R and 5-HT3A receptors was confirmed by molecular docking study, the affinity energy observed was -8.7 and -9.1 kcal/mol, respectively. CONCLUSION: Thus, this study adds new evidence and highlights that chalcone can potentially be used to develop compounds with anxiolytic properties.

Asunto(s)

Ansiolíticos , Chalcona , Chalconas , Animales , Ansiolíticos/farmacología , Pez Cebra , Simulación del Acoplamiento Molecular , Serotonina , Benzodiazepinas , Receptores de GABA-A

RESUMEN

General anxiety disorders are among the most prevalent mental health problems worldwide. The emergence and development of anxiety disorders can be due to genetic (30-50%) or non-genetic (50-70%) factors. Despite medical progress, available pharmacotherapies are sometimes ineffective or can cause undesirable side effects. Thus, it becomes necessary to discover new safe and effective drugs against anxiety. This study evaluated the anxiolytic effect in adult zebrafish (Danio rerio) of a natural pyrroloformamide (PFD), N-(4,5-dihydro-5-oxo-1,2-dithiolo-[4,3,b]-pyrrole-6-yl)-N-methylformamide, isolated from a Streptomyces sp. bacterium strain recovered from the ascidian Eudistoma vannamei. The complete structure of PFD was determined by a detailed NMR analysis, including 1H-13C and 1H-15N-HBMC data. In addition, conformational and DFT computational studies also were performed. A group of fishes (n = 6) was treated orally with PFD (0.1, 0.5 and 1.0 mg/mL; 20 µL) and subjected to locomotor activity and light/dark tests, as well as, acute toxicity 96 h. The involvement of the GABAergic and serotonergic (5-HT) systems was investigated using flumazenil (a silent modulator of GABA receptor) and 5-HT1, 5-HT2A/2C and 5-HTR3A/3B receptors antagonists, known as pizotifen, granisetron and cyproheptadine, respectively. PFD was nontoxic, reduced locomotor activity and promoted the anxiolytic effect in zebrafish. Flumazenil did not inhibit the anxiolytic effect of the PFD via the GABAergic system. This effect was reduced by a pretreatment with pizotifen and granisetron, and was not reversed after treatment with cyproheptadine. Molecular docking and dynamics studies confirmed the interaction of PFD with the 5-HT receptor.Communicated by Ramaswamy H. Sarma.

---

Pyrroloformamide (PFD), isolated from the marine Streptomyces sp. associated ascidian Eudistoma vannamei, showed no toxicity in adult zebrafish but reduced its locomotor activity.The structural elucidation of PFD was determined by the analysis of 1D and 2D NMR and HRESIMS data.The density functional theory (DFT) study confirmed the existence of two conformers as determined by NMR spectra.The serotonergic system modulated the anxiolytic effect of PFD via the 5-HT receptor in adult zebrafish.Molecular docking and dynamics studies confirmed the interaction of PFD with the 5-HT receptor.

Asunto(s)

Ansiolíticos , Animales , Ansiolíticos/farmacología , Ansiolíticos/uso terapéutico , Pez Cebra , Serotonina , Flumazenil/farmacología , Pizotilina , Simulación del Acoplamiento Molecular , Granisetrón , Ciproheptadina

RESUMEN

Anxiety-related mental health problems are estimated at 3.6% globally, benzodiazepines (BZDs) are the class of drugs indicated for the treatment of anxiety, including lorazepam and diazepam. However, concerns have been raised about the short- and long-term risks associated with BZDs. Therefore, despite anxiolytic and antidepressant drugs, there is a need to develop more effective pharmacotherapies with fewer side effects than existing drugs. The present work reported the synthesis, anxiolytic activity, mechanism of action in Adult Zebrafish (Danio rerio) and in silico study of a europium metallic complex with Lapachol, [Eu(DBM)3. LAP]. Each animal (n = 6/group) was treated intraperitoneally (i.p.; 20 µL) with the synthesized complex (4, 20 and 40 mg/Kg) and with the vehicle (DMSO 3%; 20 µL), being submitted to the tests of locomotor activity and 96h acute toxicity. The light/dark test was also performed, and the serotonergic mechanism (5-HT) was evaluated through the antagonists of the 5-HTR1, 5-HTR2A/2C and 5-HTR3A/3B receptors. The complex was characterized using spectrometric techniques, and the anxiolytic effect of complex may be involved the neuromodulation of receptors 5-HT3A/3B, since the pre-treatment with pizotifen and cyproheptadine did not block the anxiolytic effect of [Eu(DBM)3. LAP], unlike fluoxetine had its anxiolytic effect reversed. In addition, molecular docking showed interaction between the [Eu(DBM)3. LAP] and 5HT3A receptor with binding energy -7.8 kcal/mol and the ADMET study showed that complex has low toxic risk. It is expected that the beginning of this study will allow the application of the new anxiolytic drugs, given the pharmacological potential of the lapachol complex.Communicated by Ramaswamy H. Sarma.

Asunto(s)

Ansiolíticos , Naftoquinonas , Animales , Ansiolíticos/farmacología , Ansiolíticos/uso terapéutico , Pez Cebra , Europio , Simulación del Acoplamiento Molecular , Benzodiazepinas

RESUMEN

Repeated exposure to psychosocial stress modulates the endocannabinoid system, particularly anandamide (AEA) signaling in brain regions associated with emotional distress. The mTOR protein regulates various neuroplastic processes in the brain disrupted by stress, including adult hippocampal neurogenesis. This kinase has been implicated in multiple effects of cannabinoid drugs and the anti-stress behavioral effects of psychoactive drugs. Therefore, our hypothesis is that enhancing AEA signaling via pharmacological inhibition of the fatty acid amide hydrolase (FAAH) enzyme induces an anti-stress behavioral effect through an mTOR-dependent mechanism. To test this hypothesis, male C57Bl6 mice were exposed to social defeat stress (SDS) for 7 days and received daily treatment with either vehicle or different doses of the FAAH inhibitor, URB597 (0.1; 0.3; 1 mg/Kg), alone or combined with rapamycin. The results suggested that URB597 induced an inverted U-shaped dose-response curve in mice subjected to SDS (with the intermediate dose of 0.3 mg/kg being anxiolytic, and the higher tested dose of 1 mg/Kg being anxiogenic). In a second independent experiment, rapamycin treatment induced an anxiogenic-like response in control mice. However, in the presence of rapamycin, the anxiolytic dose of URB597 treatment failed to reduce stress-induced anxiety behaviors in mice. SDS exposure altered the hippocampal expression of the mTOR scaffold protein Raptor. Furthermore, the anxiogenic dose of URB597 decreased the absolute number of migrating doublecortin (DCX)-positive cells in the dentate gyrus, suggesting an anti-anxiety effect independent of newly generated/immature neurons. Therefore, our results indicate that in mice exposed to repeated psychosocial stress, URB597 fails to counteract the anxiogenic-like response induced by the pharmacological dampening of mTOR signaling.

Asunto(s)

Ansiolíticos , Ratones , Masculino , Animales , Ansiolíticos/farmacología , Sirolimus , Ratones Endogámicos C57BL , Endocannabinoides/farmacología , Serina-Treonina Quinasas TOR , Amidohidrolasas , Receptor Cannabinoide CB1

RESUMEN

BACKGROUND: Clove volatile oil (CVO) and its major compound, eugenol (EUG), have anxiolytic effects, but their clinical use has been impaired due to their low bioavailability. Thus, their encapsulation in nanosystems can be an alternative to overcome these limitations. OBJECTIVES: This work aims to prepare, characterize and study the anxiolytic potential of CVO loaded-nanoemulsions (CVO-NE) against anxious-like behavior in adult zebrafish (Danio rerio). METHODS: The CVO-NE was prepared using Agaricus blazei Murill polysaccharides as stabilizing agent. The drug-excipient interactions were performed, as well as colloidal characterization of CVO-NE and empty nanoemulsion (B-NE). The acute toxicity and potential anxiolytic activity of CVO, EUG, CVO-NE and B-NE against adult zebrafish models were determined. RESULTS: CVO, EUG, CVO-NE and B-NE presented low acute toxicity, reduced the locomotor activity and anxious-like behavior of the zebrafish at 4 - 20 mg kg-1. CVO-NE reduced the anxious-like behavior of adult zebrafish without affecting their locomotor activity. In addition, it was demonstrated that anxiolytic activity of CVO, EUG and CVO-NE is linked to the involvement of GABAergic pathway. CONCLUSION: Therefore, this study demonstrates the anxiolytic effect of CVO, in addition to providing a new nanoformulation for its administration.

Asunto(s)

Ansiolíticos , Aceites Volátiles , Syzygium , Animales , Aceite de Clavo/farmacología , Aceite de Clavo/metabolismo , Aceites Volátiles/farmacología , Pez Cebra , Syzygium/metabolismo , Ansiolíticos/farmacología , Ansiolíticos/metabolismo , Eugenol/farmacología , Eugenol/metabolismo

RESUMEN

Anxiety is a serious mental disorder, and recent statistics have determined that 35.12% of the global population had an anxiety disorder during the COVID-19 pandemic. A mechanism associated with anxiolytic effects is related to nicotinic acetylcholine receptor (nAChR) agonists, principally acting on the α4ß2 nAChR subtype. nAChRs are present in different animal models, including murine and teleosteos ones. Zebrafish has become an ideal animal model due to its high human genetic similarities (70%), giving it high versatility in different areas of study, among them in behavioral studies related to anxiety. The novel tank diving test (NTT) is one of the many paradigms used for studies on new drugs related to their anxiolytic effect. In this work, an adult zebrafish was used to determine the behavioral effects of 3- and 5-halocytisine derivatives, using the NTT at different doses. Our results show that substitution at position 3 by chlorine or bromine decreases the time spent by the fish at the bottom compared to the control. However, the 3-chloro derivative at higher doses increases the bottom dwelling time. In contrast, substitution at the 5 position increases bottom dwelling at all concentrations showing no anxiolytic effects in this model. Unexpected results were observed with the 5-chlorocytisine derivative, which at a concentration of 10 mg/L produced a significant decrease in bottom dwelling and showed high times of freezing. In conclusion, the 3-chloro and 3-bromo derivatives show an anxiolytic effect, the 3-chlorocytisine derivative being more potent than the 3-bromo derivative, with the lowest time at the bottom of the tank at 1mg/L. On the other hand, chlorine, and bromine at position 5 produce an opposite effect.

Asunto(s)

Ansiolíticos , COVID-19 , Buceo , Humanos , Animales , Ratones , Pez Cebra , Bromo , Cloro , Pandemias , Conducta Animal , Ansiolíticos/farmacología , Ansiedad/tratamiento farmacológico , Agonistas Nicotínicos/farmacología

RESUMEN

The negative impact on worldwide social well-being by the increasing rate of psychiatric diseases has led to a continuous new drug search. Even though the current therapeutic options exert their activity on multiple neurological targets, these have various adverse effects, causing treatment abandonment. Recent research has shown that Coriandrum sativum offers a rich source of metabolites, mainly terpenes and flavonoids, as useful agents against central nervous system disorders, with remarkable in vitro and in vivo activities on models related to these pathologies. Furthermore, studies have revealed that some compounds exhibit a chemical interaction with γ-aminobutyric acid, 5-hydroxytryptamine, and N-methyl-D-aspartate receptors, which are key components in the pathophysiology associated with psychiatric and neurological diseases. The current clinical evaluations of standardized extracts of C. sativum are scarce; however, one or more of its compounds represents an area of opportunity to test the efficacy of the plant as an anxiolytic, antidepressant, antiepileptic, or sleep enhancer. For this, the aim of the review was based on the pharmacological activities offered by the compounds identified and isolated from coriander and the processes involved in achieving their effect. In addition, lines of technological research, like molecular docking and nanoparticles, are proposed for the future development of phytomedicines, based on the bioactive molecules of C. sativum, for the treatment of psychiatric and neurological disorders addressed in the present study.

Asunto(s)

Ansiolíticos , Coriandrum , Trastornos Mentales , Humanos , Coriandrum/química , Simulación del Acoplamiento Molecular , Ansiolíticos/farmacología , Ansiolíticos/uso terapéutico , Antidepresivos/farmacología , Antidepresivos/uso terapéutico , Antidepresivos/metabolismo , Trastornos Mentales/tratamiento farmacológico , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéutico , Extractos Vegetales/metabolismo

RESUMEN

Increased activity in the insula has been consistently reported to be associated with anxiety and anxiety-related disorders. However, little is known on how the insula regulates anxiety. The present study aims at determining the role of the insula on the effects of glucocorticoids in anxiety. A combination of pharmacological manipulations, including blockade of adrenal GC synthesis by metyrapone and intra-insular microinjections of corticosterone, corticosterone-BSA, mineralocorticoid receptor (MR) antagonist spironolactone and glucocorticoid receptor (GR) antagonist mifepristone, were used to assess the short-term (5 min) effects of intra-insular corticosterone in two anxiety-like behaviors in male Sprague-Dawley rats. The elevated plus maze (EPM) and Novelty Suppressed Feeding (hyponeophagia) were utilized. We found that corticosterone in the insula is sufficient to prevent the anxiolytic effects corticosterone synthesis blockade in anxiety, and that intra-insular corticosterone has anxiolytic or anxiogenic effects depending on the amount of corticosterone microinjected and the arousal associated to the test, without affecting the HPA axis. Glucocorticoid anxiolytic effects in the insula are mediated by MRs, while its anxiogenic effects are dependent on a mifepristone-sensitive membrane-bound mechanism. Anxiety appears to be modulated at the insula through a competition between fast MR-dependent anxiolytic and membrane-associated anxiogenic signaling pathways that orchestrate the behavioral response to stress and determines the resulting level of anxiety.

Asunto(s)

Ansiolíticos , Glucocorticoides , Ratas , Animales , Masculino , Glucocorticoides/farmacología , Glucocorticoides/metabolismo , Corticosterona/metabolismo , Ansiolíticos/farmacología , Mifepristona/farmacología , Sistema Hipotálamo-Hipofisario/metabolismo , Ratas Sprague-Dawley , Receptores de Glucocorticoides/metabolismo , Sistema Hipófiso-Suprarrenal/metabolismo , Ansiedad/tratamiento farmacológico , Ansiedad/metabolismo , Antagonistas de Receptores de Mineralocorticoides/farmacología , Receptores de Mineralocorticoides/metabolismo

RESUMEN

Several pieces of evidence suggest that the monoaminergic theory of depression cannot fully explain all behavioral and neuroplastic changes observed after antidepressant chronic treatment. Other molecular targets, such as the endocannabinoid system, have been associated with the chronic effects of these drugs. In the present study, we hypothesized that the behavioral and neuroplastic effects observed after repeated treatment with the antidepressants (AD) Escitalopram (ESC) or venlafaxine (VFX) in chronically stressed mice depend on CB1 receptor activation. Male mice submitted to the chronic unpredictable stress (CUS) paradigm for 21 days were treated with Esc (10 mg/kg) or VFX (20 mg/kg) once a day in the presence or not of AM251 (0.3 mg/kg), a CB1 receptor antagonist/inverse agonist. At the end of the CUS paradigm, we conducted behavior tests to evaluate depressive- and anxiety-like behaviors. Our results demonstrated that chronic blockade of the CB1 receptor does not attenuate the antidepressant- or the anxiolytic-like effects of ESC nor VFX. ESC increased the expression of CB1 in the hippocampus, but AM251 did not change the pro-proliferative effects of ESC in the dentate gyrus or the increased expression of synaptophysin induced by this AD in the hippocampus. Our results suggest that CB1 receptors are not involved in behavioral and hippocampal neuroplastic effects observed after repeated antidepressant treatment in mice submitted to CUS.

Asunto(s)

Ansiolíticos , Agonismo Inverso de Drogas , Ratones , Masculino , Animales , Antidepresivos/farmacología , Antidepresivos/metabolismo , Hipocampo/metabolismo , Depresión/tratamiento farmacológico , Endocannabinoides/metabolismo , Ansiolíticos/farmacología , Clorhidrato de Venlafaxina/farmacología , Estrés Psicológico/tratamiento farmacológico , Estrés Psicológico/metabolismo , Receptor Cannabinoide CB1/metabolismo

RESUMEN

Donkey milk (DM) is a source of bioactive compounds that can benefit neural functioning. In the present study, we investigated the effects of DM consumption on anxiolytic-related, despair-like, locomotion and coordination behaviors, as well as the provision of protection from oxidative damage to lipids and proteins in brain tissues and melatonin plasma levels. To achieve this, male mice orally received DM (4 g.kg-1) or vehicle for 18 days. Their behavior was assessed in the following tests: elevated plus maze (EPM), open field and rotarod tests (OF, RR) and forced swimming test (FST). Acute treatments with diazepam (DZP, 1.5 mg.kg-1, v.o.), fluoxetine (FLX, 20 mg.kg-1, i.p.) and nortriptyline (NTP, 20 mg.kg-1, i.p.) were used as positive controls. On the eighteenth day, the animals were euthanized and brain tissue and blood were collected to measure oxidative damage, and melatonin plasma levels. Similar to DZP, repeated DM consumption reduced exploration to open areas in the EPM test. Under our experimental conditions, conventional antidepressants reduced immobility time in the FST, and the benzodiazepine treatment impaired motor coordination in mice. No significant differences in locomotion, motor coordination and despair-related behaviors were observed in the mice treated with DM when assessed in the EPM, OF, RR and FST, respectively. Biochemical assays showed that repeated DM exposition protected against oxidative damage to lipids and increased plasma levels of melatonin. These findings suggest consumption of DM may be a promising food for the treatment of anxiety-related disorders, without depressant effects on the central nervous system.

Asunto(s)

Ansiolíticos , Lesiones Encefálicas , Melatonina , Ratones , Masculino , Animales , Melatonina/farmacología , Leche , Ansiedad/tratamiento farmacológico , Ansiedad/metabolismo , Ansiolíticos/farmacología , Encéfalo , Estrés Oxidativo , Natación , Lípidos , Conducta Animal , Depresión/metabolismo