RESUMO
Anxiety and depression are common mental disorders affecting millions of people worldwide. Unsatisfactory clinical outcomes with the use of the available pharmacological interventions among some patients demand newer drugs with proven efficacy, safety, and tolerability profile. In this study, the LQFM211, LQFM213, and LQFM214 were designed from the piperazine scaffold and administered orally in mice. These mice were later evaluated in the open field, elevated plus maze, and forced swimming tests to assess the exploratory, anxiolytic, and antidepressant-like activities, respectively. The mechanism of action of these new derivatives was evaluated using flumazenil (benzodiazepine antagonist) and WAY100635 (5-HT1A receptor antagonist). Unlike LQFM214, the LQFM211 and LQFM213 elicited anxiolytic and antidepressant-like effects. The blockade of the effect of LQFM213 by WAY100635 suggests the involvement of the serotonergic pathway.
Assuntos
Ansiolíticos , Animais , Ansiolíticos/farmacologia , Ansiolíticos/uso terapêutico , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Comportamento Animal , Humanos , Camundongos , Piperazina/farmacologia , Antagonistas da Serotonina/farmacologia , Antagonistas da Serotonina/uso terapêutico , Relação Estrutura-AtividadeRESUMO
Transcriptomics, proteomics and pathogen-host interactomics data are being explored for the in silico-informed selection of drugs, prior to their functional evaluation. The effectiveness of this kind of strategy has been put to the test in the current COVID-19 pandemic, and it has been paying off, leading to a few drugs being rapidly repurposed as treatment against SARS-CoV-2 infection. Several neglected tropical diseases, for which treatment remains unavailable, would benefit from informed in silico investigations of drugs, as performed in this work for Dengue fever disease. We analyzed transcriptomic data in the key tissues of liver, spleen and blood profiles and verified that despite transcriptomic differences due to tissue specialization, the common mechanisms of action, "Adrenergic receptor antagonist", "ATPase inhibitor", "NF-kB pathway inhibitor" and "Serotonin receptor antagonist", were identified as druggable (e.g., oxprenolol, digoxin, auranofin and palonosetron, respectively) to oppose the effects of severe Dengue infection in these tissues. These are good candidates for future functional evaluation and clinical trials.
Assuntos
Antivirais/uso terapêutico , Dengue/tratamento farmacológico , Transcriptoma , Adenosina Trifosfatases/antagonistas & inibidores , Antagonistas Adrenérgicos/farmacologia , Antagonistas Adrenérgicos/uso terapêutico , Antivirais/farmacologia , Encéfalo/metabolismo , Simulação por Computador , Dengue/sangue , Dengue/genética , Dengue/metabolismo , Descoberta de Drogas , Avaliação Pré-Clínica de Medicamentos , Reposicionamento de Medicamentos , Humanos , Fígado/metabolismo , Redes e Vias Metabólicas/efeitos dos fármacos , NF-kappa B/metabolismo , Antagonistas da Serotonina/farmacologia , Antagonistas da Serotonina/uso terapêutico , Dengue Grave/sangue , Dengue Grave/tratamento farmacológico , Dengue Grave/genética , Dengue Grave/metabolismo , Baço/metabolismoRESUMO
Previously the effects (0.01-3.0â¯mg/kg) of post-training SB-699551 (a 5-HT5A receptor antagonist) were reported in the associative learning task of autoshaping, showing that SB-699551 (0.1â¯mg/kg) decreased lever-press conditioned responses (CR) during short-term (STM; 1.5-h) or (3.0â¯mg/kg) long-term memory (LTM; 24-h); relative to the vehicle animals. Moreover, as pro-cognitive efficacy of SB-699551 was reported in the ketamine-model of schizophrenia. Hence, firstly aiming improving performance (conditioned response, CR), in this work autoshaping lever-press vs. nose-poke response was compared; secondly, new set of animals were randomly assigned to SB-699551 plus forgetting or amnesia protocols. Results show that the nose-poke operandum reduced inter-individual variance, increased CR and produced a progressive CR until 48-h. After one week of no training/testing sessions (i.e., interruption of 216â¯h), the forgetting was observed; i.e., the CR% of control-saline group significantly decreased. In contrast, SB-699551 at 0.3 and 3.0â¯mg/kg prevents forgetting. Additionally, as previously reported the non-competitive NMDA receptor antagonist dizocilpine (0.2â¯mg/kg) or the non-selective cholinergic antagonist scopolamine (0.3â¯mg/kg) decreased CR in STM. SB-699551 (0.3â¯mg/kg) alone also produced amnesia-like effect. Co-administration of SB-699551-dizocilpine or SB-699551-scopolamine reversed the SB-699551 induced-amnesic effects in LTM (24-h). Nose-poke seems to be a reliable operandum. The anti-amnesic and anti-forgetting mechanisms of amnesic SB-699551-dose remain unclear. The present findings are consistent with the notion that low doses of 5-HT5A receptor antagonists might be useful for reversing memory deficits associated to forgetting and amnesia. Of course, further experiments are necessary.
Assuntos
Amnésia/metabolismo , Memória/fisiologia , Receptores de Serotonina/metabolismo , Antagonistas da Serotonina/uso terapêutico , Amnésia/induzido quimicamente , Amnésia/tratamento farmacológico , Análise de Variância , Animais , Compostos de Bifenilo/uso terapêutico , Antagonistas Colinérgicos/toxicidade , Condicionamento Clássico/efeitos dos fármacos , Condicionamento Operante/efeitos dos fármacos , Modelos Animais de Doenças , Maleato de Dizocilpina/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Comportamento Exploratório/efeitos dos fármacos , Extinção Psicológica/efeitos dos fármacos , Masculino , Memória/efeitos dos fármacos , Ratos , Ratos Wistar , Escopolamina/toxicidadeRESUMO
Ketamine (KET) is a non-competitive N-Methyl-d-aspartate (NMDA) receptors antagonist that intensifies sensory experiences, prompts hallucinations and delusions, exacerbates previously installed psychosis and disrupts physiological evoked potentials (AEPs). Pharmacologically, KET stimulates glutamate efflux in the medial prefrontal cortex, mainly in the prelimbic (PrL) sub-region. Efferences from this region exert a top-down regulatory control of bottom-up sensory processes either directly or indirectly. In the midbrain, the central nucleus of the inferior colliculus (CIC) plays a fundamental role in the processing of auditory ascending information related to sound localization, sensorimotor gating, and preattentive event-related potentials. Auditory hallucinations elicited during a psychotic outbreak are accompanied by CIC neural activation. Thus, it is possible that NMDA-mediated glutamate neurotransmission in the PrL indirectly modulates CIC neuronal firing. The aim of the present study was to assess the effects of KET on the latency and amplitude of AEPs elicited in the CIC of rats tested during KET effects and following withdrawal from the chronic administration. Changes on emotionally induced by KET treatment were evaluated with the use of the elevated zero maze (EZM). Unlike typical neuroleptics, the atypical antipsychotic clozapine (CLZ) potently blocks the disruption of the sensorimotor gating induced by NMDA antagonists. Therefore, the effects of KET withdrawal on AEPs were challenged with a systemic injection of CLZ. In addition, we further investigated the role of NMDA receptors of the PrL on the AEPs expression recorded in the CIC through intra-PrL infusions of NMDA itself. Our results showed that the processing of sensory information in the CIC is under indirect control of PrL. These data suggest that the long-term KET treatment disrupts the collicular auditory field potentials, possibly through influencing PrL glutamate activity on intrinsic 5-HT mechanisms in the dorsal raphe and CIC.
Assuntos
Clozapina/uso terapêutico , Potenciais Evocados Auditivos/fisiologia , Ketamina/toxicidade , Córtex Pré-Frontal/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Síndrome de Abstinência a Substâncias/metabolismo , Animais , Clozapina/farmacologia , Potenciais Evocados Auditivos/efeitos dos fármacos , Antagonistas de Aminoácidos Excitatórios/toxicidade , Masculino , Microinjeções/métodos , Córtex Pré-Frontal/efeitos dos fármacos , Ratos , Ratos Wistar , Receptores de N-Metil-D-Aspartato/agonistas , Antagonistas da Serotonina/farmacologia , Antagonistas da Serotonina/uso terapêutico , Síndrome de Abstinência a Substâncias/tratamento farmacológicoRESUMO
A series of phenylselanyl-1H-1,2,3-triazole-4-carbonitriles with different substituents were screened for their binding affinity with serotonin transporter (SERT) and dopamine transporter (DAT) by docking molecular. 5-(4methoxyphenyl)-1-(2-(phenylselanyl)phenyl)-1H-1,2,3-triazole-4-carbonitrile (SeTACN) exhibited the best conformation with SERT even higher than fluoxetine and serotonin, suggesting a competitive inhibition. SeTACN demonstrated additional affinity to other serotonergic receptors involved in antidepressant effects: 5HT1a, 5HT2a and 5HT3. In another set of experiments, SeTACN led to significant reductions in the immobility time of mice submitted to forced swimming test (FST) in the dose range of 0.1- 20mg/kg, suggesting an antidepressant-like effect. The possible mechanism of action was investigated using serotonergic and dopaminergic antagonists. The antidepressant-like effect of SeTACN (0.1mg/kg i.g.) was prevented by the pretreatment with WAY100635 (a selective 5HT1a antagonist), ketanserin (a 5HT2a/c antagonist) and ondansetron (a selective 5ht3 antagonist), PCPA (an inhibitor of serotonin synthesis) but not with SCH23390 (dopaminergic D1 antagonist) and sulpiride (D2 antagonist). Sub-effective dose of fluoxetine was able to potentiate the effects of a sub-effective dose of SeTACN in FST. None of the treatments affected locomotor activity in open field test (OFT). These results together, suggest that the SeTACN antidepressant-like effect is mediate, at least in parts, by serotonergic system.
Assuntos
Antidepressivos/uso terapêutico , Compostos Organosselênicos/farmacologia , Serotonina/fisiologia , Triazóis/farmacologia , Animais , Relação Dose-Resposta a Droga , Masculino , Camundongos , Modelos Moleculares , Antagonistas da Serotonina/uso terapêutico , Agonistas do Receptor de Serotonina/uso terapêutico , NataçãoRESUMO
In the current study, carrageenan (CG; 100-1000 µg/site) was injected intraorally in the cheeks of Holtzman or Wistar rats to evaluate the consequences of administration of a non-immunogenic stimulus in the orofacial region. Subsequent inflammation was measured as oedema (increased thickness of the cheek wall using digital calipers), relative to the other cheek injected with saline. Oedema formation and tissue collection for histopathological studies were assessed at 0.5, 1, 2, 3, 4, 6, 24, 48, 72, 96, 120 and 144 h after injection. In parallel, other groups of rats were injected with CG in the hind paw, to provide a reference response. The inhibitor of prostaglandin biosynthesis, indomethacin, and antagonists of histamine, serotonin and NK1 receptors were injected s.c., 0.5 h before CG. CG induced a dose-related oedema more rapidly from 0 to 2 h which lasted for at least 72 h, showing a biphasic profile (peak at 2 and 24 h), compared with the monophasic oedema induced in rat paws (maximal duration of 24 h). Histopathological analysis of the CG-injected cheek revealed oedema formation with little leukocyte recruitment at 1-3 h, mast cell degranulation at 6 h, and a mixed polymorphonuclear and mononuclear cell infiltrate by 24 h. Histamine and serotonin antagonists and indomethacin, but not the NK1 antagonist, decreased cheek oedema in the first 4 h following carrageenan. Taken together, our data indicated important differences in the pattern of inflammation between the oral cavity and the paw which will determine the therapeutic approach to the treatment of inflammatory conditions in the oral cavity.
Assuntos
Carragenina/administração & dosagem , Modelos Animais de Doenças , Edema/imunologia , Boca/imunologia , Animais , Bochecha , Relação Dose-Resposta a Droga , Edema/induzido quimicamente , Edema/metabolismo , Edema/prevenção & controle , Antagonistas dos Receptores Histamínicos/administração & dosagem , Antagonistas dos Receptores Histamínicos/uso terapêutico , Indometacina/administração & dosagem , Indometacina/uso terapêutico , Boca/efeitos dos fármacos , Boca/metabolismo , Antagonistas dos Receptores de Neurocinina-1/administração & dosagem , Antagonistas dos Receptores de Neurocinina-1/uso terapêutico , Ratos Sprague-Dawley , Ratos Wistar , Antagonistas da Serotonina/administração & dosagem , Antagonistas da Serotonina/uso terapêuticoRESUMO
OBJECTIVES: To examine the skeletal effects of chronic psychostimulant treatment in children and adolescents. STUDY DESIGN: Medically healthy 5- to 17-year-old males from 4 different clinic-based studies were combined for this analysis. They were divided by psychostimulant use into 3 groups: none to negligible, intermittent, and continuous use. Most (95%) had also received risperidone for 6 months or more. Treatment history was extracted from medical and pharmacy records. Anthropometric and bone measurements, using dual-energy x-ray absorptiometry and peripheral quantitative computed tomography, were obtained at each research visit. Multivariable linear regression analysis models examined whether age-sex-specific height Z-score and skeletal outcomes differed among the 3 psychostimulant-use groups. RESULTS: The sample consisted of 194 males with a mean age of 11.7 ± 2.8 years at study entry. The majority had an externalizing disorder. There was no significant difference across the 3 treatment groups in height Z-score or in skeletal outcomes at the radius, lumbar spine, or whole body. One hundred forty-four boys had valid follow-up skeletal data 1.4 ± 0.7 years after study entry. Again, neither height Z-score nor the skeletal outcomes were different among those who remained on psychostimulants between the 2 visits, started psychostimulants anew, or had not taken psychostimulants. CONCLUSIONS: Following chronic treatment, psychostimulants did not appear to significantly affect bone mass accrual in children and adolescents taking risperidone. There was a small, but statistically not significant, negative impact on longitudinal growth.
Assuntos
Osso e Ossos/efeitos dos fármacos , Osso e Ossos/fisiologia , Psicotrópicos/farmacologia , Risperidona/farmacologia , Antagonistas da Serotonina/farmacologia , Absorciometria de Fóton , Adolescente , Criança , Pré-Escolar , Estudos Transversais , Quimioterapia Combinada , Humanos , Masculino , Transtornos Mentais/tratamento farmacológico , Psicotrópicos/uso terapêutico , Risperidona/uso terapêutico , Antagonistas da Serotonina/uso terapêutico , Tomografia Computadorizada por Raios XRESUMO
OBJECTIVES: To compare children with primary, chronic idiopathic nausea to those with secondary nausea associated with functional abdominal pain. STUDY DESIGN: Retrospective chart review of 45 children with a primary complaint of chronic nausea several times per week. Comparisons were made to prospectively collected data on 49 children with functional abdominal pain and comorbid nausea. RESULTS: The majority of those affected were adolescent Caucasian females. Subjects with chronic nausea had a more severe presentation with daily 88% (vs 26%) and constant 60% (vs 10%) nausea (P < .001), one-half with peak morning intensity. In the chronic nausea group, 62% had migraines, and 71% (vs 22%) had familial migraines (P < .001), 36% had postural tachycardia syndrome and 27% cyclic vomiting syndrome. Both groups suffered comorbid symptoms (anxiety, dizziness, fatigue, and sleep problems). The chronic nausea cohort underwent extensive, negative medical evaluations. CONCLUSIONS: Chronic idiopathic nausea of childhood is a poorly described symptom. Patients with primary (vs secondary) chronic nausea were more likely Caucasian, older adolescent females with severe, daily nausea and comorbid conditions such as anxiety, dizziness, and fatigue as well as significantly more migraine features. Chronic nausea is a major, disabling symptom that requires increased recognition as a separate functional entity. Future studies may need to focus on comorbid conditions including migraine and dysautonomia.
Assuntos
Dor Abdominal/complicações , Gastroenteropatias/complicações , Náusea/etiologia , Dor Abdominal/psicologia , Adolescente , Amitriptilina/uso terapêutico , Antidepressivos Tricíclicos/uso terapêutico , Ansiedade/complicações , Criança , Doença Crônica , Feminino , Gastroenteropatias/diagnóstico , Gastroenteropatias/tratamento farmacológico , Gastroenteropatias/psicologia , Humanos , Masculino , Transtornos de Enxaqueca/complicações , Náusea/diagnóstico , Náusea/tratamento farmacológico , Náusea/psicologia , Inibidores da Bomba de Prótons/uso terapêutico , Estudos Retrospectivos , Antagonistas da Serotonina/uso terapêutico , Índice de Gravidade de DoençaRESUMO
The antinociceptive role of spinal 5-HT5A receptors in rat models of pain along with their expression was evaluated in the spinal cord and dorsal root ganglion (DRG). Nociception was assessed in the formalin, capsaicin, and acetic acid writhing tests. The expression of 5-HT5A receptors was determined by Western blot analysis. Intrathecal treatment with serotonin (5-HT, 10-100 nmol) or 5-carboxamidotryptamine (5-CT, 0.03-0.3 nmol) dose-dependently prevented 1% formalin-induced nociception. Furthermore, 5-HT reduced capsaicin- and acetic acid-induced nociception. 5-HT- or 5-CT-induced antinociception in the formalin test was diminished by the selective 5-HT5A receptor antagonist N-[2-(dimethylamino)ethyl]-N-[[4'-[[(2-phenylethyl)amino] methyl][1,1'-biphenyl]-4-yl]methyl]cyclopentanepropanamide dihydrochloride (SB-699551; 3 and 10 nmol). In addition, 5-HT-induced spinal antinociception in the capsaicin and acetic acid tests was blocked by SB-699551 (10 nmol). Given alone, intrathecal injection of SB-699551 did not affect nociception induced by any irritant. 5-HT5A receptors were expressed in the dorsal spinal cord and DRG, even though formalin injection increased after 24h 5-HT5A receptor expression only in the spinal cord. Data suggest that 5-HT and 5-CT produce antinociception by activation of spinal 5-HT5A receptors in both the spinal cord and DRG. Furthermore, our results suggest that spinal 5-HT5A receptors play an antinociceptive role in several pain models in rats. 5-HT5A receptors may provide a therapeutic target to develop analgesic drugs.
Assuntos
Dor/induzido quimicamente , Dor/tratamento farmacológico , Receptores de Serotonina/efeitos dos fármacos , Serotonina , Medula Espinal/metabolismo , Ácido Acético , Animais , Capsaicina , Feminino , Medição da Dor , Ratos , Ratos Wistar , Receptores de Serotonina/biossíntese , Serotonina/análogos & derivados , Serotonina/farmacologia , Antagonistas da Serotonina/uso terapêutico , Agonistas do Receptor de Serotonina/farmacologia , Medula Espinal/efeitos dos fármacosRESUMO
BACKGROUND: Negative symptoms and cognitive deficits are two partially-related features of schizophrenia which have a major negative impact on social function and objective quality of life. Standard drug treatments have little impact on either. There is some evidence that anti-inflammatory treatment may have beneficial effects in schizophrenia and major depression. Statins are cholesterol-lowering agents that have been found to be anti-inflammatory agents and are also known to decrease C-reactive protein (CRP). Ondansetron is a serotonin (5-HT3) receptor antagonist widely used to prevent nausea and vomiting in patients receiving chemotherapy for cancer. Small studies have suggested that ondansetron is effective as an adjunct drug in improving the symptoms of schizophrenia. METHODS/DESIGN: This is a two center, six-month, double-blind placebo controlled, factorial design study of ondansetron and/or simvastatin added to treatment as usual for patients suffering from schizophrenia, schizoaffective disorder, psychosis not otherwise specified or schizophreniform disorder. This will be a 2 × 2 design, with 54 patients in each cell, giving a total of 216 patients over three years. There will be a screening, a randomization and seven follow-up visits. Full clinical and neurocognitive assessments will be carried out at baseline (randomization), 14 weeks and at 26 weeks, while the positive and negative syndrome scale (PANSS), pill count and side effects checklist will be carried out at every visit. Simvastatin will be started at 20 mg once daily (OD), this will be increased to 40 mg after four weeks. Ondansetron will be administered in an 8 mg dose. DISCUSSION: Anti-inflammatory treatments have been shown to have some beneficial effects in schizophrenia. Both simvastatin and ondansetron provide some evidence of a reduction in symptoms compared to treatment as usual. The aim of this study is to establish the degree of improvement in negative symptoms with the addition of ondansetron and/or simvastatin to treatment as usual. TRIAL REGISTRATION: [corrected] ClinicalTrials.gov NCT01602029.