RESUMO
Arylpiperazine clubbed various heterocyclic molecules present potential pharmacophoric structural features for the development of psychoactive drugs. There are various CNS active molecules possessing arylpiperazine moiety in their pharmacophore approved by USFDA. In the current study, we have explored the benzhydrylpiperazine moiety clubbed with various substituted oxadiazole moieties (AP1-12) for their monoamine oxidase (MAO) inhibition and antidepressant potential. Compounds AP3 and AP12 exhibited highly potent and selective MAO-A inhibition with IC50 values of 1.34 ± 0.93 µM and 1.13 ± 0.54 µM, respectively, and a selectivity index of 10- and 13-folds, respectively. Both the compounds displayed reversible binding character at the active site of MAO-A. In further in vivo evaluation, both the compounds AP3 and AP12 displayed potential antidepressant-like character in FST and TST studies via significantly reduced immobility time in comparison to non-treated animals. These compounds displayed no cytotoxicity in SH-SY5Y cell lines, which indicates that these compounds are safe for further evaluation. In silico studies reveal that synthesized compounds possess drug-likeness with minimal to no toxicity. In silico studies were conducted to understand the binding interactions and stability of compounds at the binding pocket of enzyme and observed that both the best compounds fit well at the active site of MAO-A lined by amino acid residues Tyr69, Asn181, Phe208, Ile335, Leu337, Phe352, and Tyr444 similar to standard MAO-A inhibitor clorgiline. The molecular dynamic studies demonstrated that AP3 and AP12 formed quite a stable complex at the active site of MAO-A and did not break under small abruption forces. The favourable binding interactions and appropriate ADMET properties present the benzhydrylpiperazine clubbed oxadiazole pharmacophoric features as a potential structural skeleton for further clinical evaluation and development of a new antidepressant drug molecule.
Assuntos
Neuroblastoma , Farmacóforo , Animais , Humanos , Antidepressivos/farmacologia , Inibidores da Monoaminoxidase/química , Monoaminoxidase/metabolismo , Relação Estrutura-AtividadeRESUMO
Bipolar disorder (BD) is a severe and common chronic mental illness characterized by recurrent mood swings between depression and mania. The biological basis of the disease is poorly understood, and its treatment is unsatisfactory. Na+, K+-ATPase is a major plasma membrane transporter and signal transducer. The catalytic α subunit of this enzyme is the binding site for cardiac steroids. Three α isoforms of the Na+, K+-ATPase are present in the brain. Previous studies have supported the involvement of the Na+, K+-ATPase and endogenous cardiac steroids (ECS) in the etiology of BD. Decreased brain ECS has been found to elicit anti-manic and anti-depressive-like behaviors in mice and rats. However, the identity of the specific α isoform involved in these behavioral effects is unknown. Here, we demonstrated that decreasing ECS through intracerebroventricular (i.c.v.) administration of anti-ouabain antibodies (anti-Ou-Ab) decreased the activity of α1+/- mice in forced swimming tests but did not change the activity in wild type (wt) mice. This treatment also affected exploratory and anxiety behaviors in α1+/- but not wt mice, as measured in open field tests. The i.c.v. administration of anti-Ou-Ab decreased brain ECS and increased brain Na+, K+-ATPase activity in wt and α1+/- mice. The serum ECS was lower in α1+/- than wt mice. In addition, a study in human participants demonstrated that serum ECS significantly decreased after treatment. These results suggest that the Na+, K+-ATPase α1 isoform is involved in depressive- and manic-like behaviors and support that the Na+, K+-ATPase/ECS system participates in the etiology of BD.
Assuntos
Depressão , ATPase Trocadora de Sódio-Potássio , Esteroides , Animais , Humanos , Camundongos , Ratos , Depressão/metabolismo , Ouabaína/metabolismo , Isoformas de Proteínas/metabolismo , ATPase Trocadora de Sódio-Potássio/genética , ATPase Trocadora de Sódio-Potássio/metabolismo , Esteroides/metabolismoRESUMO
Prescription drug abuse is an issue that is rapidly growing globally. Pregabalin, an anticonvulsant, analgesic, and anxiolytic medication, is effective in the management of multiple neurological disorders; however, there is increasing concern regarding its widespread illicit use. It has been previously reported in mice that pregabalin can induce conditioned place preference. In this current investigation, the potential of pregabalin to elicit free-choice drinking in a mouse model of drug addiction, and its effect on recognition and withdrawal behaviors after forced abstinence, were studied. Twenty-two male BALB/c mice were randomly divided into three groups (n = 7-8/group); control, pregabalin-30, and pregabalin-60. The study had three phases: habituation (days 1-5) with free water access, free-choice drinking (days 6-13) with pregabalin groups receiving one water and one pregabalin bottle, and forced abstinence (days 14-21) with free water access. On day 13, the first open field test was conducted, followed by the Novel Object Recognition Test. On day 21, the second open field test was performed, followed by the Tail Suspension Test and Forced Swimming Test. Pregabalin elicited voluntary drinking in the higher-dose group, concurrently causing a decline in recognition memory performance in the novel object recognition test. Moreover, pregabalin induced withdrawal behavior after a period of forced abstinence in the forced swimming and tail suspension tests. This is the first report to establish an animal model of free-choice pregabalin drinking that may be used for further molecular studies and targeted therapy for pregabalin addiction.
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The first-generation antihistamine chlorpheniramine (CPA) is believed to have both anxiolytic and antidepressant properties. The current study sought to assess the mechanisms behind the antidepressant and anxiolytic effects of CPA therapy concerning oxidative stress, inflammation, and nuclear factor p45 for erythroid 2-Brain-derived neurotrophic factor (Nrf2-BDNF) signaling pathway in forced swimming-induced depressive-like behavior and anxiety. Eighteen male Wistar rats (180-200 gm) rats were separated into three groups (n = 6): a stressed group (acute stress) that underwent the forced swimming test (FST) and a stressed group that received pretreatment with CPA (10 mg/kg body weight) for 3 weeks (CPA + acute stress). Animals were subsequently put through the following behavioral tests after undergoing a forced swim test (FST) for 5 min: an immobility test, open field test, and elevated plus maze test. Serum cortisol levels were measured when the rats were euthanized at the end of the experiments. Brain neurotransmitters (cortisol, serotonin, and noradrenaline), oxidative stress (SOD and MDA), inflammatory (IL-6 and IL-1) biomarkers, and the Nrf2-BDNF signaling pathway in the hippocampus and cerebral cortex tissues was determined. CPA prevented stress-induced increases in cortisol levels (p < 0.0001), decreased brain neurotransmitters, and increased oxidative stress and inflammation. CPA also upregulated the Nrf2-BDNF signaling pathway. Thus, CPA mitigates depressive-like behavior and anxiety by inhibiting oxidative stress and inflammation and upregulating the Nrf2-BDNF signaling pathway in the brain tissues.
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7-substituted tetrahydroisoquinolines derivatives were designed, synthesized, and evaluated for neuroprotective properties. We summarized the preliminary structure activity relationships (SAR). Compound 3i was screened as a hit compound and its antidepressant activity was evaluated by employing the forced swimming test, tail suspension test. Additionally, ADMET profile (absorption, distribution, metabolism, excretion and toxicity properties) of the compound 3i was predicted in order to evaluate their lead-like properties and safety. The interaction of compound 3i bound to MAO-A was explored using molecular docking and molecular dynamics simulation. Results of biological studies revealed that the compound 3i exhibited almost equal antidepressant activity compared with magnoflorine. Compound 3i is predicted to possess good drug like properties and safety based on ADMET profile predictions. This work provides ideas for the drugs discovery of antidepressant agents.
Assuntos
Antidepressivos , Tetra-Hidroisoquinolinas , Simulação de Acoplamento Molecular , Natação , Relação Estrutura-AtividadeRESUMO
The novel series of substituted-N-(5,6-diphenyl-1,2,4-triazin-3-yl) benzamides (R: 1-12) were designed, synthesized and evaluated for in-vitro and in-vivo antidepressant-like activity. In MAO-A inhibition assay, compound R: 5 and R: 9 displayed most potent activity with IC50 = 0.12 and 0.30 µM. R: 5 and R: 9 were also evaluated for in-vivo antidepressant using FST and TST. In both models, the test samples R: 5 and R: 9 showed noteworthy antidepressant effect. R: 5 showed 46.48 % and 45.96 % reduction in immobility in FST and TST respectively at dosage of 30 mg/kg (p.o). Whereas compound R: 9 reduced the immobility time by 52.76 % and 47.14 % as compared to control in FST and TST, respectively at same dosage. Both the compounds were also tested for behavioural study using actophotometer and grip tests. None of compounds exhibited decrease in locomotor activity. Further, these compounds were subjected to in silico studies to determine their ADME properties along with binding energies and binding orientions. In ADME studies none of the compounds violated the Lipinski rule and all other parameters were also within the acceptable ranges. In docking study R: 5 (-10.7) and R: 9 (-10.4) were also displayed highest docking score. These encouraging results present the pharmacophoric features of substituted-N-(5,6-diphenyl-1,2,4-triazin-3-yl) benzamides as interesting lead for further development of new antidepressant drug molecules.
Assuntos
Antioxidantes , Natação , Antioxidantes/farmacologia , Antidepressivos/farmacologia , Antidepressivos/química , Triazinas/farmacologia , BenzamidasRESUMO
Several studies reported that rabbiteye blueberry (Vaccinium ashei Reade) leaves present promising biological properties. To the best of our knowledge, no study investigated the possible application of their hydroalcoholic extract for treating mood disorders. Herein, we evaluated if the hydroalcoholic extract of rabbiteye blueberry (Vaccinium ashei Reade) leaves (HEV) promotes an antidepressant-like effect in rodents using chronic experimental approaches. The effect of repeated administration of HEV (50â mg/kg, p.o.) on the immobility time was assessed in the forced swimming test (FST) in an unpredictable chronic mild stress (UCMS) model. Repeated treatment with HEV reversed the depressive-like behavior induced by UCMS by reducing the immobility time. Besides, the exposure to HEV caused no changes in relative organ weights in rats submitted to UCMS. The results indicated that HEV administration presented antidepressant-like action devoid of toxic effects. Thus, it is possible to suggest its potential as a safe and accessible therapeutic tool in the management of depression and other related mood disorders.
Assuntos
Mirtilos Azuis (Planta) , Ratos , Animais , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêuticoRESUMO
PURPOSE: Central fatigue plays an important role in reducing endurance exercise activity during brain development. c-Fos gene expression in the hippocampus was examined as an indicator of neuronal activation after exhaustion. METHODS: Eighteen pre-pubertal male rats at four weeks old and 18 adult rats at eight weeks were randomly divided into three groups: Control (C), Constant time exercise (CTEx), Endurance Exercise until Exhaustion (ExhEx), which started at two minutes and ended in 20 min, the main swimming test was performed with a weight equal to 5% of the bodyweight attached to the rats' tail as a single session in experimental groups and was recorded at the end of their time, while to evaluate the force loss, the Grip strength was measured before and after the activity. The brain activation rate was examined by c-Fos gene expression and Nissl staining in CA3 and dentate gyrus (DG) in the hippocampus of all groups. RESULTS: Power grip and Nissl positive neurons in CA3 and DG have been significantly higher in pre-pubertal rats than in adults, both in the CTEx group (p = 0.04) and in the ExhEx group (p < 0.001). Also, real-time exhaustion in the pre-pubertal group was significantly longer than in adults. c-Fos gene expression was significantly reduced in adults' hippocampus in comparison to preadolescence (p < 0.01) and control (p < 0.001). CONCLUSION: These findings clarified that increased strength and longer fatigue in pre-puberal rats may lead to c-Fos gene expression and decreased neurons in the hippocampus. Perhaps this is a protective effect to suppress stress hormones.
Less force loss and longer real-time exhaustion in pre-pubertal subjects.There was no significant reduction in c-Fos gene expression in the hippocampus of pre-pubertal rats after exhaustion.The Nissl positive neurons in CA3 and DG of the Hippocampus are significantly lower in the exhausted adult rat in comparison with the pre-pubertal group.
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In the pathogenesis of depression, heredity is believed to be a major factor. However, the mechanism by which heredity contributes to the onset of depression is not fully understood. Wistar Kyoto (WKY) rats have been used as an animal model for depression because of their increased depression-like behavior compared to Wistar (WIS) rats. In the present study, pups crossbred from WKY × WIS rats were used to evaluate locomotor activity in an open field test (OFT) and depression-like behavior in a forced swimming test (FST), with a focus on amino acid metabolism. Pups in the WKYâ × WKYâ group showed lower locomotor activity in the OFT and higher depression-like behavior in the FST than those in the WISâ × WISâ group. In addition, multiple regression analysis showed that the paternal strain had a greater effect than the maternal strain on locomotor activity and depression-like behavior in OFT and FST, respectively. Several amino acids in the brainstem, hippocampus, and striatum were significantly decreased through the influence of the WKY paternal strain, but not the WKY maternal strain. Based on these data from comparing WKY and WIS rats, we hypothesize that the hereditary effects of the WKY paternal strain on behavioral tests are partially caused by dysregulation of the amino acid metabolism in the brain.
Assuntos
Encéfalo , Depressão , Ratos , Animais , Ratos Endogâmicos WKY , Ratos Wistar , Depressão/patologia , Natação , Modelos Animais de DoençasRESUMO
Encouraged by the potent anti-depression activities of incensole (1) and incensole acetate (2) isolated from the resin of Boswellia papyrifera in our previous work, different derivatives of 1 and 2 were synthesized in the present study. The reaction of 1 with m-CPBA afforded the mono-epoxide derivative 3a, while the same reaction with 2 led to three different epoxide derivatives 3a, 3b, and 3c. Oxidation of 1 with PCC to get compound 3b, however along with the target 3b, the reaction gave three interesting side products (3c-3e). Oxime (3b-1) resulted from the reaction of 3b with hydroxylamine hydrochloride in pyridine, while epoxidation of 2 generate three epoxide products (4a-4c). The structures of all products were unambiguously confirmed using NMR and Mass spectrometry. Compounds 3a-e and 4a-c (0.1-3 mg/kg, i.p.) demonstrated promising anti-depression activities in classical mouse models of depression of FST and TST. The results showed that compounds 3a-e and 4a-c (0.1-3 mg/kg, i.p.) caused dose dependent reduction in immobility time compared to the vehicle control, with 3c-3e and 4b-4c demonstrating higher potency and efficacy. The findings of the open field test excluded the motor effects of these compounds, thus further confirming their anti-depression activity. Preliminary investigation into their mechanism of action using GABA antagonist, PTZ and molecular docking has predicted that compounds 3e and 4c bind at the GABA binding site of GABAA receptor to produce GABAergic effects. Furthermore, the promising anti-depression potency of compounds 1 and 2 and their derivatives make them lead compounds for drug discovery.
Assuntos
Boswellia , Franquincenso , Animais , Boswellia/química , Diterpenos , Compostos de Epóxi , Camundongos , Simulação de Acoplamento Molecular , Receptores de GABA-ARESUMO
The present work was undertaken to investigate the effects of acute forced swimming (FS) on the levels of brain-derived neurotrophic factor (BDNF) and tyrosine kinase receptor B (trkB) proteins in: the ventral tegmental area (VTA); the nucleus accumbens (Acb) shell and core compartments; and the anterior cingulate (ACg), prelimbic (PL) and infralimbic (IL) territories of the prefrontal cortex of genetic models of vulnerability (RLA, Roman low-avoidance rats) and resistance (RHA, Roman high-avoidance rats) to stress-induced depression. We report for the first time that FS induced very rapid and distinct changes in the levels of BDNF and trkB proteins in different areas of the mesocorticolimbic system of RHA and RLA rats. Thus, (1) in the VTA and Acb core, FS elicited a significant increase of both BDNF- and trkB-LI in RHA but not RLA rats, whereas in the Acb shell no significant changes in BDNF- and trkB-LI across the line and treatment were observed; (2) in RLA rats, the basal levels of BDNF-LI in the IL/PL cortex and of trkB-LI in the ACg cortex were markedly lower than those of RHA rats; moreover, BDNF- and trkB-LI in the IL/PL and ACg cortex were increased by FS in RLA rats but decreased in their RHA counterparts. These results provide compelling evidence that the genetic background influences the effects of stress on BDNF/trkB signaling and support the view that the same stressor may impact differently on the expression of BDNF in discrete brain areas.
Assuntos
Fator Neurotrófico Derivado do Encéfalo , Núcleo Accumbens , Ratos , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Núcleo Accumbens/metabolismo , Área Tegmentar Ventral/metabolismo , Córtex Pré-Frontal/metabolismo , Córtex Cerebral/metabolismo , Receptor trkB/genética , Receptor trkB/metabolismoRESUMO
Sigma-1 receptor (σ1R) ligands have been shown to be effective at relieving neuropathic and inflammatory pain, but have not yet been tested in experimental models of fibromyalgia. The objective of this study was to evaluate the effect of a σ1R antagonist (BD1063) compared to pregabalin. ICR-CD1 female mice were subjected to either six repeated injections of reserpine, to cause reserpine-induced myalgia (RIM6), or acidified saline intramuscular injections (ASI). In these two models, we evaluated the effect of BD1063 and pregabalin on thermal hypersensitivity, anxiety-like and depression-like behaviors, and on spinal cord gliosis. BD1063 exerted an antinociceptive effect on both reflexive (thermal hyperalgesia) and nonreflexive (anxiety- and depression-like) pain behaviors, and reduced spinal astroglial and microglial reactivity, following repeated treatment for 2 weeks. Interestingly, the effects of BD1063 were long-term, lasting several weeks after treatment discontinuation in both fibromyalgia-like models. Similar results were obtained with pregabalin, but the effects on pain behaviors lasted for a shorter length of time, and pregabalin did not significantly modulate spinal glial reactivity. The inhibitory and long-lasting effect of pharmacological blockade of σ1Rs on both sensory and affective dimensions of nociplastic-like pain and spinal cord gliosis in two experimental models of fibromyalgia support the application of this therapeutic strategy to treat fibromyalgia.
Assuntos
Analgésicos , Dor Crônica , Fibromialgia , Receptores sigma , Analgésicos/uso terapêutico , Animais , Dor Crônica/tratamento farmacológico , Modelos Animais de Doenças , Feminino , Fibromialgia/tratamento farmacológico , Gliose , Hiperalgesia/tratamento farmacológico , Camundongos , Camundongos Endogâmicos ICR , Pregabalina/uso terapêutico , Receptores sigma/antagonistas & inibidores , Reserpina/efeitos adversos , Receptor Sigma-1RESUMO
Medicinal plants belonging to the Verbenaceae family demonstrated antidepressant effects in preclinical studies. Depression is one of the largest contributors to the global health burden of all countries. Plants from the Aloysia genus are traditionally used for affective disorders, and some of them have proven anxiolytic and antidepressant activity. The aim of this work was to evaluate the antidepressant effect of the ethanolic extract of Aloysia gratissima var. gratissima (Agg) and Aloysia virgata var. platyphylla (Avp) in mice. A tail suspension test (TST) and forced swimming test (FST) were conducted after three doses in a period of 24 h and after 7 days of treatment. Imipramine was used as an antidepressant drug. The main results demonstrated that Agg extract reduced the immobility time in mice treated orally for 7 consecutive days when compared to the control group (reduced by about 77%, imipramine 70%). Animals treated with three doses of Avp in a 24-h period had reduced immobility time in the FST (60%), and after 7 days of treatment the reduction was greater (Avp 50, 100, and 200 about 85%; Avp 400, 96.5%; p < 0.0001, imipramine, 77%). LCMS analysis showed the presence of verbascoside, hoffmaniaketone, and hoffmaniaketone acetate in both, A. virgata var. platyphylla and A. gratissima var gratissima. The flavonoids nepetin and 6-hydroxyluteolin were also found in Agg. Both tested extracts demonstrated promising antidepressant-like activity in mice.
Assuntos
Etanol , Verbenaceae , Camundongos , Animais , Imipramina/farmacologia , Extratos Vegetais/uso terapêutico , Verbenaceae/química , Antidepressivos/farmacologia , Antidepressivos/uso terapêuticoRESUMO
The antidepressant activity of (+) and (-)-paeoveitol was first evaluated using the forced swimming test (FST), and (+)-paeoveitol showed potential antidepressant activity by decreasing immobility time of mice (by approximately 26.4%) in the FST at a dose of 20 mg/kg. To explore the structure-activity relationships (SARs) and obtain more potent compounds, twenty derivatives of (+)-paeoveitol were synthesized and evaluated for their agonistic activities on melatonin type I (MT1) and type II (MT2) receptors. As a results, compound 13 with an N-methylpiperazine fragment exhibited obvious effect on MT1 and MT2 receptors with EC50 values of 0.20 and 0.24 mM. Moreover, compound 13 dose-dependently decreased the immobility of mice in the FST and showed an inverted U-shaped dose-effect, and the most efficacious dose (at 40 mg/kg) was comparable to fluoxetine (20 mg/kg) with a reduced immobility time of 29.2% and 34.5%, respectively. In vivo neurochemical assays suggested that compound 13 obviously increased 5-hydroxytryptamine (5-HT), 5-hydroxyindoleacetic acid (5-HIAA) and norepinephrine (NE) levels in the mice brain, indicating that its antidepressant effects might be related to the monoaminergic system. In silico ADMET study revealed that 13 has favorable pharmacokinetic properties. These findings suggest that compound 13 could be a potential antidepressant agent. Graphical abstract.
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Addiction to various drugs and chemicals is a significant public health concern worldwide. Addiction to prescription medications has increased due to the psychoactive effects of these medications, their availability, low price, and the lack of legal consequences for abusers. One of such prescription medication is mirtazapine (MIRT). MIRT is an antidepressant that has recently been reported to be abused and could induce withdrawal symptoms in different case studies. No previous study has investigated its abuse potential in animal models of drug addiction. Here, we conducted a free-choice drinking paradigm to investigate voluntary drinking of MIRT at two different concentrations. Male BALB/c mice were given unlimited access to two water bottles for five days before being divided into three groups: the first group had free access to two water bottles. The second group (MIRT10) and the third group (MIRT20) was allowed unlimited choice to one bottle of water and one bottle of MIRT at concentrations of 0.03 and 0.06 mg/mL, respectively. The average daily MIRT intake in the MIRT20 group was significantly higher on all tested days than that in the MIRT10 group. Moreover, mice in the MIRT20 group preferred to self-administer MIRT over water, indicating that MIRT can induce drug-seeking behavior. To further investigate the addictive potential of MIRT and its possible deterioration of memory and recognition, as reported with several known drugs of abuse, animals underwent a novel object recognition test. Mice in the MIRT20 group demonstrated significant deterioration in memory and recognition, indicating its effects on different brain regions involved in recognition, similar to other known drugs of abuse. The forced swimming test and tail suspension test were used to test MIRT-induced withdrawal symptoms after forced abstinence. After eight days of abstinence, mice in the MIRT20 group demonstrated significant depression-like symptoms in both the TST and FST, manifested by a significant increase in immobility time. MIRT was shown to induce drug-seeking behavior, deteriorate recognition, and cause withdrawal symptoms. This might confirm that MIRT has the potential to induce drug dependence and further studies are warranted to explore the neurobiological basis of MIRT-induced drug-seeking behavior.
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The search for natural ingredients that have a certain nutritional value and contribute to the preservation of human health is a very urgent task. The goal of this research was to study the effect of three viscous extracts - two polymalt and one malt extract, on the psychophysiological functions of animals in an experiment with prolonged consumption. Material and methods. The study was conducted on white mongrel male rats weighing 110-130 g, divided into 4 groups of 13 individuals. The 1st group (control) received standard granulated feed without extracts, the 2nd group - the feed with a polymalt grain extract from barley, hulless oats and wheat, the 3rd group - the feed with a polymalt grain extract from barley, hulless oats and rye, the 4th group - the feed with a malt extract from barley grain, in a dose of 2.1 g/kg of body weight. The consumption of the studied extracts in all groups of animals lasted 21 days. The animals were weighed before and after the consumption period and tested using the "Open field" test (research and motor activity were recorded), the «Rotating Rod¼ test (study of locomotor reactions), «Forced Swimming¼ (study of induced depression). Results. The addition of malt and polymalt extracts to the diet of the experimental animals had a beneficial effect on them: the duration of fading as an indicator of depression during swimming test in all experimental rats decreased by 31.4-37.8% with varying degrees of statistical significance. At the same time, a monomalt extract from barley grain and a polymalt extract from grain of barley, naked oats, and rye had a more positive effect on the condition of the animals in the experiment: in the "Rotating Rod" test, the retention time of animals as an indicator of endurance increased by 26.0-27.1%; in the «Open Field¼ test, motor and exploratory activity increased and the time of passive behavior decreased by 35.0-37.4%. Conclusion. The development, production and research of malt extracts is a promising direction that requires the selection of initial grain components taking into account their chemical composition. It is possible to create general restorative supplements on the basis of extracts, as well as to introduce them into alcoholic beverages in order to reduce the toxicity of ethyl alcohol and preserve a number of physiological functions in the human body during alcohol consumption.
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Dieta , Hordeum , Humanos , Masculino , Animais , Ratos , Suplementos Nutricionais , Peso Corporal , Alérgenos , Grão Comestível , Extratos Vegetais/farmacologiaRESUMO
INTRODUCTION: The interleukin-6/janus kinase 2/signal transducer and activator of transcription 3 (IL-6/JAK2/STAT3) pathway plays an important role in immune function, but little research has focused on this pathway in depression. We sought to examine the relationship between the IL-6/JAK2/STAT3 pathway and depressive-like behavior. METHODS: Using a chronic mild stress (CMS) paradigm, a total of 36 adult male Sprague-Dawley rats were divided into four matched groups: (1) control + vehicle, (2) CMS + vehicle, (3) control + paroxetine, and (4) CMS + paroxetine. We investigated the effects of CMS on depressive-like behavior by using the forced swimming test (FST). Subsequently, the mRNA levels of members of the IL-6/JAK2/STAT3 pathway were assessed by qRT-PCR. RESULTS: We found that rats exposed to CMS displayed a significant increase in immobility time and a decrease in climbing time in the FST. Moreover, mRNA levels of IL-6, JAK2, and STAT3 in the hypothalamus were increased following CMS. We also found that mRNA levels of IL-6, JAK2, and STAT3 were normalized by paroxetine administration, which coincided with normalization of the depressive-like behavior. CONCLUSIONS: The IL-6/JAK2/STAT3 pathway may be activated in depression, and targeting this pathway may provide a novel effective therapeutic approach for the treatment of depression.
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Janus Quinase 2 , Fator de Transcrição STAT3 , Animais , Hipotálamo/metabolismo , Interleucina-6 , Janus Quinase 2/metabolismo , Masculino , Ratos , Ratos Sprague-Dawley , Fator de Transcrição STAT3/metabolismo , Transdução de SinaisRESUMO
Hypothyroidism causes somatic, psychosocial and affective psychosis, including depression-like behaviors. In this study, (hypothyroidism group; HP group) adult male Sprague Dawley (SD) rats were induced to hypothyroidism after 5 weeks of exposure to 0.05% propylthiouracil (PTU) in potable water, control animals (CON group) were given the same amount of water. The following behavioral experiments were conducted, respectively: open-field test (OFT), forced swimming test (FST), tail suspension test (TST). TT[Formula: see text] and TT[Formula: see text] levels were measured after the behavior tests and the expression levels of 5-HT[Formula: see text] receptor and 5-HT[Formula: see text] receptor proteins were analyzed in the hippocampus and prefrontal cortex. The level of TT[Formula: see text] and TT[Formula: see text] in the HP group rats was much lower than that in the CON group. The hypothyroid rats also showed weight loss, much longer immobility time in tail suspension test and forced swimming test. Besides, 5 weeks of PTU administration was associated with significantly decreased expression levels of 5-HT[Formula: see text] receptor and 5-HT[Formula: see text] receptor proteins compared with control group, which were significantly negatively correlated with immobility time in FST and TST. In conclusion, our results suggest that hypothyroidism induces depressive behaviors through the influence of the serotonin system, and the decreased expression of the 5-HT[Formula: see text] receptor is an important cause of the depressive behaviors in hypothyroidism.
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Depressão , Hipotireoidismo , Animais , Comportamento Animal , Depressão/etiologia , Hipotireoidismo/induzido quimicamente , Hipotireoidismo/complicações , Masculino , Ratos , Ratos Sprague-Dawley , Receptor 5-HT2A de Serotonina , Serotonina , NataçãoRESUMO
Based on the potent antidepressant and anticonvulsant activities of the triazole-containing quinolinones reported in our previous work, a series of ring-opened derivatives of them were designed, synthesized in this work. Their antidepressant and anticonvulsant activities were screened using the forced swimming test (FST) and the maximal electroshock seizure test (MES), respectively. The results showed that compounds 4a, 5a, 6c-6e, 6g-6i, and 7 led to significant reductions in the accumulated immobility time in the FST at a dose of 50 mg/kg. Especially compound 7 exhibited higher levels of efficacy than the reference standard fluoxetine in the FST and the tail suspension test. The results of an open field test excluded the possibility of central nervous stimulation of 7, which further confirmed its antidepressant effect. Meanwhile, compounds 6a-6i and 7 showed different degrees of anticonvulsant activity in mice at the doses range from 300 to 30 mg/kg in the MES. Among them, compounds 6e and 7 displayed the ED50 of 38.5 and 32.7 mg/kg in the MES, and TD50 of 254.6 and 245.5 mg/kg, respectively. No one showed neurotoxicity at the dose of 100 mg/kg. The preliminary investigation forward to their mechanism indicated that regulation of GABAergic system might contribute to their anticonvulsive and anti-depressive action.
Assuntos
Anticonvulsivantes/farmacologia , Antidepressivos/farmacologia , Depressão/tratamento farmacológico , Quinolonas/farmacologia , Convulsões/tratamento farmacológico , Triazóis/farmacologia , Animais , Anticonvulsivantes/síntese química , Anticonvulsivantes/química , Antidepressivos/síntese química , Antidepressivos/química , Relação Dose-Resposta a Droga , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos , Estrutura Molecular , Quinolonas/síntese química , Quinolonas/química , Relação Estrutura-Atividade , Natação , Triazóis/químicaRESUMO
Cannabidiol (CBD), a phytocannabinoid compound, presents antidepressant and anxiolytic-like effects in the type-1 diabetes mellitus(DM1) animal model. Although the underlying mechanism remains unknown, the type-1A serotonin receptor (5-HT1A) and cannabinoids type-1 (CB1) and type-2 (CB2) receptors seem to play a central role in mediating the beneficial effects on emotional responses. We aimed to study the involvement of these receptors on an antidepressant- and anxiolytic-like effects of CBD and on some parameters of the diabetic condition itself. After 2 weeks of the DM1 induction in male Wistar rats by streptozotocin (60 mg/kg; i.p.), animals were treated continuously for 2-weeks with the 5-HT1A receptor antagonist WAY100635 (0.1 mg/kg, i.p.), CB1 antagonist AM251 (1 mg/kg i.p.) or CB2 antagonist AM630 (1 mg/kg i.p.) before the injection of CBD (30 mg/kg, i.p.) or vehicle (VEH, i.p.) and then, they were submitted to the elevated plus-maze and forced swimming tests. Our findings show the continuous treatment with CBD improved all parameters evaluated in these diabetic animals. The previous treatment with the antagonists - 5-HT1A, CB1, or CB2 - blocked the CBD-induced antidepressant-like effect whereas only the blockade of 5-HT1A or CB1 receptors was able to inhibit the CBD-induced anxiolytic-like effect. Regarding glycemic control, only the blockade of CB2 was able to inhibit the beneficial effect of CBD in reducing the glycemia of diabetic animals. These findings indicated a therapeutic potential for CBD in the treatment of depression/anxiety associated with diabetes pointing out a complex intrinsic mechanism in which 5-HT1A, CB1, and/or CB2 receptors are differently recruited.