RESUMEN

The growing proximity of wildlife to large urban niches arouses greater interest in understanding wild reservoirs in the epidemiology of diseases of importance to animal and human health. The aim of the present study was to investigate the presence of piroplasmids in opossums rescued from the metropolitan region of Rio de Janeiro state, Brazil. Blood and bone marrow samples were collected from 15 Didelphis aurita and subjected to DNA extraction and PCR using primers for the 18S rRNA, cox1, cox3, and hsp70 genes of piroplasmids. Clinical and hematological evaluation of the animals was also performed. Five (33.3%) of the 15 opossums tested positive for piroplasms in the nested PCR based on the 18S rRNA, and in two animals, it was possible to observe intra-erythrocytic structures compatible with merozoites. One of the positive animals showed clinical signs of infection such as jaundice, fever, and apathy. Anemia, low level of plasma protein, leukocytosis, and regenerative erythrocyte signs were observed in positive animals. Phylogenetic analysis based on both 18S rRNA and cox-3 genes demonstrated that the piroplasmids detected in D. aurita formed a unique sub-clade, albeit related to piroplasmids previously detected in Didelphis albiventris and associated ticks from Brazil. This study proposes the novel Piroplasmida Clade, namely "South American Marsupialia Group," and reinforces the need for new clinical-epidemiological surveys to understand the dynamics of these infections in didelphids in Brazil.

Asunto(s)

Didelphis , Marsupiales , Piroplasmida , Animales , Humanos , Filogenia , Brasil/epidemiología , Piroplasmida/genética , ARN Ribosómico 18S/genética

RESUMEN

There is a growing concern about the participation of wild hosts and reservoirs in the epidemiology of several pathogens, particularly within the context of environmental changes and the expansion of the One Health concept. The aim of this study was to investigate the presence of hemoplasmas in opossums rescued from the metropolitan region of Rio de Janeiro state, Brazil. Blood samples were collected from 15 Didelphis aurita and subjected to DNA extraction and PCR using primers for the 16S rRNA and 23S rRNA genes. Physical examination and hematological analysis were also performed. Three out of 15 opossums tested positive for hemotropic Mycoplasma spp. by PCR and showed hematological alterations such as anemia and leukocytosis. Clinical signs were non-specific and associated to traumatic lesions. The phylogenetic analysis indicated that the hemoplasma detected was positioned between 'Ca. Mycoplasma haemodidelphis' detected in D. virginiana from North American and hemoplasmas recently detected in D. aurita from the state of Minas Gerais, Brazil. This study indicates the existence of hemoplasma infections in D. aurita from the metropolitan region of Rio de Janeiro, and reinforce the need for new epidemiological inquiries to clarify the participation of these in the dynamics of circulation of tick-borne pathogens.

Asunto(s)

Didelphis , Marsupiales , Infecciones por Mycoplasma , Mycoplasma , Animales , Brasil/epidemiología , Filogenia , ARN Ribosómico 16S/genética , Mycoplasma/genética , Genotipo , Infecciones por Mycoplasma/diagnóstico , Infecciones por Mycoplasma/epidemiología , Infecciones por Mycoplasma/veterinaria

RESUMEN

There is a growing concern about the participation of wild hosts and reservoirs in the epidemiology of several pathogens, particularly within the context of environmental changes and the expansion of the One Health concept. The aim of this study was to investigate the presence of hemoplasmas in opossums rescued from the metropolitan region of Rio de Janeiro state, Brazil. Blood samples were collected from 15 Didelphis aurita and subjected to DNA extraction and PCR using primers for the 16S rRNA and 23S rRNA genes. Physical examination and hematological analysis were also performed. Three out of 15 opossums tested positive for hemotropic Mycoplasma spp. by PCR and showed hematological alterations such as anemia and leukocytosis. Clinical signs were non-specific and associated to traumatic lesions. The phylogenetic analysis indicated that the hemoplasma detected was positioned between 'Ca. Mycoplasma haemodidelphis' detected in D. virginiana from North American and hemoplasmas recently detected in D. aurita from the state of Minas Gerais, Brazil. This study indicates the existence of hemoplasma infections in D. aurita from the metropolitan region of Rio de Janeiro, and reinforce the need for new epidemiological inquiries to clarify the participation of these in the dynamics of circulation of tick-borne pathogens.(AU)

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Há uma crescente preocupação com a participação de hospedeiros e reservatórios silvestres na epidemiologia de diversos patógenos, principalmente no contexto das mudanças ambientais e da expansão do conceito "One Health". O objetivo deste estudo foi investigar a presença de hemoplasmas em gambás resgatados da região metropolitana do estado do Rio de Janeiro, Brasil. Amostras de sangue foram coletadas de 15 Didelphis aurita e submetidas à extração de DNA e PCR utilizando-se "primers" para os genes 16S rRNA e 23S rRNA. O exame físico e a análise hematológica também foram realizados. Três dos 15 gambás testaram positivo para Mycoplasma spp. hemotrópico por PCR. Os sinais clínicos eram inespecíficos e associados a lesões traumáticas. Anemia e leucocitose foram detectadas em animais positivos. A análise filogenética indicou que o hemoplasma detectado estava posicionado entre 'Ca. Mycoplasma haemodidelphis' detectado em D. virginiana da América do Norte e hemoplasmas recentemente detectados em D. aurita do estado de Minas Gerais, Brasil. Este estudo indica a existência de infecções por hemoplasmas em D. aurita, da região metropolitana do Rio de Janeiro, e reforça a necessidade de novos inquéritos epidemiológicos, para esclarecer a participação destes na dinâmica de circulação de patógenos transmitidos por carrapatos.(AU)

Asunto(s)

Animales , Didelphis/genética , Brasil , Mycoplasma , Infecciones por Mycoplasma/genética

RESUMEN

This randomized clinical trial aimed to evaluate different fluid therapy protocols associated with inhalational or total intravenous anesthesia in the cardiorespiratory stability of bitches with sepsis subjected to a surgical procedure to control the infectious focus. Thirty-two bitches diagnosed with pyometra and sepsis and treated at the University Veterinary Hospital between 2018 and 2019 were recruited. After admission, diagnosis, clinical, and laboratory evaluation, patients were randomly distributed into the following groups: propofol 5 (P[5]: preoperative restrictive fluid therapy-5mL/kg/h and intravenous general anesthesia); propofol 10 (P[10]: preoperative liberal fluid therapy-10mL/kg/h and intravenous general anesthesia); and isoflurane 5 (I[5]: preoperative restrictive fluid therapy-5mL/kg/h and inhalational general anesthesia). Lactate on admission (LAC1) and release (LAC2), heart rate (HR), respiratory rate (RR), systolic blood pressure (SBP), rectal temperature (RT), oxygen saturation (SpO2), and carbon dioxide extraction rate (EtCO2) were analyzed at PRE, T10, T20, T30, T40, T50, TEXT, and TDIS. Clearance of 20% of lactate occurred in 18 dogs, with the P[10] group displaying the best performance. There was no statistical difference in vasopressor requirements among the groups. Liberal fluid therapy showed greater cardiovascular stability than restrictive therapy in the perioperative period. Regarding general anesthesia, isoflurane showed greater cardiorespiratory stability than propofol during anesthetic maintenance. In conclusion, although the three proposed protocols are safe and there is no difference in their superiority, some observed changes may be relevant and considered when it is possible to individualize the therapy for the patient.

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Este ensaio clínico randomizado teve a proposição de avaliar diferentes protocolos de fluidoterapia associados a anestesia inalatória ou total intravenosa, na estabilidade hemodinâmica de cadelas com sepse, submetidas a procedimento cirúrgico, para controle do foco infeccioso. Foram incluídas trinta e duas cadelas, com diagnóstico de piometra e sepse, atendidas em hospital veterinário universitário, no período de 2018 a 2019. Após admissão, diagnóstico, avaliação clínica e laboratoriais, os pacientes foram distribuídos de maneira aleatória nos grupos Propofol 5 (P[5]: fluidoterapia restritiva pré-operatória - 5mL/kg/h e anestesia geral intravenosa), Propofol 10 (P[10]: fluidoterapia liberal pré-operatória - 10mL/kg/h e anestesia geral intravenosa) e Isoflurano 5 (I[5]: fluidoterapia restritiva pré-operatória - 5mL/kg/h e anestesia geral inalatória). Foram analisados lactato na admissão (LAC1) e liberação (LAC2), frequências cardíacas (HR) e respiratória (RR), pressão arterial sistólica (SBP), temperatura retal (RT), saturação de oxigênio (SpO2) e taxa de extração de dióxido de carbono (EtCO2) nos seguintes momentos: PRE, T10, T20, T30, T40, T50, TEXT e TDIS. A depuração de 20% do lactato ocorreu em 18 cães, tendo o grupo P[10] o melhor desempenho. Não houve diferença estatística no requerimento de vasopressores entre os grupos. A fluidoterapia liberal apresentou maior estabilidade cardiovascular quando comparado com a restritiva no período perioperatório. Com relação a anestesia geral, o isoflurano apresentou maior estabilidade cardiorrespiratória que o propofol na manutenção anestésica. Nós concluímos que apesar de os três protocolos propostos serem seguros e sem diferença em superioridade entre eles, algumas alterações observadas podem ser relevantes e ponderadas quando for possível a individualização da terapêutica no paciente.

RESUMEN

Trypanosoma spp. infection is a problem in many tropical countries, infecting several animal species, including humans. The aim of the present study was to identify the Trypanosoma species in Neotropical primates from Rio de Janeiro state and compare the results with other reports both phylogenetically and geographically. Molecular detection was based on the 18 SSU gene. The sequences obtained in the PCR were sequenced and compared with others previously deposited in GenBank. These sequences were used to perform phylogenetic analysis and make a distribution map of primate species infected by Trypanosoma species in Brazil. Among 34 monkeys, five capuchin monkeys (Sapajus spp.) and one marmoset (Callithrix spp.) showed Trypanosoma spp. sequences in the same clade of Trypanosoma minasense and three capuchin monkeys' sequences were in the same clade of Trypanosoma cruzi. The Atlantic Forest and the Brazilian Amazon are the regions with the highest frequency of studies about Trypanosoma spp. and variety of Neotropical primate hosts. These are areas that deserve attention regarding the conservation of biodiversity, but it also makes evident the lack of studies with Neotropical primates in other regions of the country, as well as multidisciplinary studies to better understand the host pathogen relationships.

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A infecção por Trypanosoma spp. é um problema em muitos países tropicais, infectando várias espécies animais, incluindo humanos. O objetivo do presente estudo foi identificar as espécies de Trypanosoma em primatas neotropicais no estado Rio de Janeiro e comparar os resultados com outros relatos, tanto filogeneticamente quando geograficamente. A detecção molecular foi baseada no gene SSU 18. As sequências obtidas na PCR foram sequenciadas e comparadas com outras previamente depositadas no GenBank. Essas sequências foram utilizadas para análises filogenéticas e confeccionar um mapa de distribuição de espécies de primatas infectadas por espécies de Trypanosoma no Brasil. Entre 34 macacos, cinco macacos-prego (Sapajus spp.) e um sagui (Callithrix spp.) apresentaram sequências de Trypanosoma spp. no mesmo clado de Trypanosoma minasense e três sequências de macacos-prego estavam no mesmo clado de Trypanosoma cruzi. A Mata Atlântica e a Amazônia brasileira são as regiões com maior frequência de estudos sobre Trypanosoma spp. e variedade de primatas neotropicais hospedeiros. São áreas que merecem atenção no que se refere à conservação da biodiversidade, mas também evidencia a carência de estudos com PNH em outras regiões do país e de estudos multidisciplinares para melhor compreender as relações do patógeno hospedeiro.

Asunto(s)

Animales , Trypanosoma/aislamiento & purificación , Tripanosomiasis/epidemiología , Callithrix , Sapajus , Enfermedades de los Monos/epidemiología , Trypanosoma cruzi , Tripanosomiasis/veterinaria

RESUMEN

Capillaria spp. infections of the urinary tract of domestic carnivores are uncommon worldwide. Infections are rarely diagnosed and are typically asymptomatic. This study aimed to evaluate a case of capillariosis in a cat from the state of Rio de Janeiro, Brazil. A seven-year-old female cat with apathy and reduced appetite was presented. Urine analysis revealed C. plica eggs in urine sediment, and cystitis was evidenced by the presence of bacteria, pyuria, proteinuria and hematuria. The subject was treated with 50 mg/kg fenbendazole for five days. Urine samples were frozen for molecular analysis and species confirmation. Polymerase chain reaction for amplification of the 18S rRNA gene followed by sequencing confirmed the occurrence of Capillaria sp. There has been limited phylogenetic study of Capillaria spp. in cats, so further studies are needed to identify the species present in different locations and associated with feline pathogenesis.

Asunto(s)

Capillaria/aislamiento & purificación , Enfermedades de los Gatos/diagnóstico , Infecciones por Enoplida/veterinaria , Infecciones Urinarias/veterinaria , Animales , Antinematodos/uso terapéutico , Brasil , Enfermedades de los Gatos/tratamiento farmacológico , Enfermedades de los Gatos/parasitología , Gatos , Infecciones por Enoplida/diagnóstico , Infecciones por Enoplida/tratamiento farmacológico , Infecciones por Enoplida/parasitología , Femenino , Fenbendazol/uso terapéutico , Resultado del Tratamiento , Infecciones Urinarias/diagnóstico , Infecciones Urinarias/tratamiento farmacológico , Infecciones Urinarias/parasitología

RESUMEN

The neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induces motor and nonmotor dysfunctions resembling Parkinson's disease (PD); however, studies investigating the effects of 1-methyl-4-phenylpyridinium (MPP+), an active oxidative product of MPTP, are scarce. This study investigated the behavioral and striatal neurochemical changes (related to oxidative damage, glial markers, and neurotrophic factors) 24 h after intracerebroventricular administration of MPP+ (1.8-18 µg/mouse) in C57BL6 mice. MPP+ administration at high dose (18 µg/mouse) altered motor parameters, since it increased the latency to leave the first quadrant and reduced crossing, rearing, and grooming responses in the open-field test and decreased rotarod latency time. MPP+ administration at low dose (1.8 µg/mouse) caused specific nonmotor dysfunctions as it produced a depressive-like effect in the forced swim test and tail suspension test, loss of motivational and self-care behavior in the splash test, anxiety-like effect in the elevated plus maze test, and short-term memory deficit in the step-down inhibitory avoidance task, without altering ambulation. MPP+ at doses of 1.8-18 µg/mouse increased tyrosine hydroxylase (TH) immunocontent and at 18 µg/mouse increased α-synuclein and decreased parkin immunocontent. The astrocytic calcium-binding protein S100B and glial fibrillary acidic protein (GFAP)/S100B ratio was decreased following MPP+ administration (18 µg/mouse). At this highest dose, MPP+ increased the ionized calcium-binding adapter molecule 1 (Iba-1) immunocontent, suggesting microglial activation. Also, MPP+ at a dose of 18 µg/mouse increased thiobarbituric acid reactive substances (TBARS) and glutathione (GSH) levels and increased glutathione peroxidase (GPx) and hemeoxygenase-1 (HO-1) immunocontent, suggesting a significant role for oxidative stress in the MPP+-induced striatal damage. MPP+ (18 µg/mouse) also increased striatal fibroblast growth factor 2 (FGF-2) and brain-derived neurotrophic factor (BDNF) levels. Moreover, MPP+ decreased tropomyosin receptor kinase B (TrkB) immunocontent. Finally, MPP+ (1.8-18 µg/mouse) increased serum corticosterone levels and did not alter acetylcholinesterase (AChE) activity in the striatum but increased it in cerebral cortex and hippocampus. Collectively, these results indicate that MPP+ administration at low doses may be used as a model of emotional and memory/learning behavioral deficit related to PD and that MPP+ administration at high dose could be useful for analysis of striatal dysfunctions associated with motor deficits in PD.

Asunto(s)

1-Metil-4-fenilpiridinio/toxicidad , Cuerpo Estriado/efectos de los fármacos , Emociones/efectos de los fármacos , Aprendizaje/efectos de los fármacos , Memoria/efectos de los fármacos , Actividad Motora/efectos de los fármacos , Acetilcolinesterasa/metabolismo , Animales , Cuerpo Estriado/metabolismo , Proteína Ácida Fibrilar de la Glía/metabolismo , Glutatión/metabolismo , Ratones , Subunidad beta de la Proteína de Unión al Calcio S100/metabolismo , Sustancias Reactivas al Ácido Tiobarbitúrico/metabolismo

RESUMEN

Ketamine has emerged as a novel strategy to treat refractory depression, producing rapid remission, but elicits some side effects that limit its use. In an attempt to investigate a safer compound that may afford an antidepressant effect similar to ketamine, this study examined the effects of the ergogenic compound creatine in a model of depression, and the involvement of phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway in its effect. In order to induce a depressive-like behavior, mice were administered with corticosterone (20 mg/kg, per os (p.o.)) for 21 days. This treatment increased immobility time in the tail suspension test (TST), an effect abolished by a single administration of creatine (10 mg/kg, p.o.) or ketamine (1 mg/kg, i.p.), but not by fluoxetine (10 mg/kg, p.o., conventional antidepressant). Treatment of mice with wortmannin (PI3K inhibitor, 0.1 µg/site, intracerebroventricular (i.c.v.)) or rapamycin (mTOR inhibitor, 0.2 nmol/site, i.c.v.) abolished the anti-immobility effect of creatine and ketamine. None of the treatments affected locomotor activity of mice. The immunocontents of p-mTOR, p-p70S6 kinase (p70S6K), and postsynaptic density-95 protein (PSD95) were increased by creatine and ketamine in corticosterone or vehicle-treated mice. Moreover, corticosterone-treated mice presented a decreased hippocampal brain-derived neurotrophic factor (BDNF) level, an effect abolished by creatine or ketamine. Altogether, the results indicate that creatine shares with ketamine the ability to acutely reverse the corticosterone-induced depressive-like behavior by a mechanism dependent on PI3K/AKT/mTOR pathway, and modulation of the synaptic protein PSD95 as well as BDNF in the hippocampus, indicating the relevance of targeting these proteins for the management of depressive disorders. Moreover, we suggest that creatine should be further investigated as a possible fast-acting antidepressant.

Asunto(s)

Conducta Animal , Creatina/uso terapéutico , Depresión/tratamiento farmacológico , Ketamina/uso terapéutico , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal/efectos de los fármacos , Serina-Treonina Quinasas TOR/metabolismo , Animales , Antidepresivos/farmacología , Antidepresivos/uso terapéutico , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Corticosterona/sangre , Creatina/administración & dosificación , Creatina/farmacología , Depresión/sangre , Depresión/patología , Modelos Animales de Enfermedad , Femenino , Fluoxetina , Ketamina/administración & dosificación , Ketamina/farmacología , Ratones , Modelos Biológicos

RESUMEN

ATP (adenosine 5'-triphosphate), one of the most ancient neurotransmitters, exerts essential functions in the brain, including neurotransmission and modulation of synaptic activity. Moreover, this nucleotide has been attributed with trophic properties and experimental evidence points to the participation of ATP-activated P2X and P2Y purinergic receptors in embryonic brain development as well as in adult neurogenesis for maintenance of normal brain functions and neuroregeneration upon brain injury. We discuss here the available data on purinergic P2 receptor expression and function during brain development and in the neurogenic zones of the adult brain, as well as the insights based on the use of in vitro stem cell cultures. While several P2 receptor subtypes were shown to be expressed during in vitro and in vivo neurogenesis, specific functions have been proposed for P2Y1, P2Y2 metabotropic as well as P2X2 ionotropic receptors to promote neurogenesis. Further, the P2X7 receptor is suggested to function in the maintenance of pools of neural stem and progenitor cells through induction of proliferation or cell death, depending on the microenvironment. Pathophysiological actions have been proposed for this receptor in worsening damage in brain disease. The P2X7 receptor and possibly additional P2 receptor subtypes have been implicated in pathophysiology of neurological diseases including Parkinson's disease, Alzheimer's disease and epilepsy. New strategies in cell therapy could involve modulation of purinergic signaling, either in the achievement of more effective protocols to obtain viable and homogeneous cell populations or in the process of functional engraftment of transplanted cells into the damaged brain. This article is part of the Special Issue entitled 'Purines in Neurodegeneration and Neuroregeneration'.

Asunto(s)

Adenosina Trifosfato/metabolismo , Encéfalo/metabolismo , Neurogénesis , Receptores Purinérgicos P2X/metabolismo , Receptores Purinérgicos P2Y/metabolismo , Animales , Encéfalo/embriología , Diferenciación Celular , Epilepsia/metabolismo , Epilepsia/terapia , Humanos , Células-Madre Neurales/metabolismo , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/terapia , Receptores Purinérgicos P2X7/metabolismo , Receptores Purinérgicos P2Y1/metabolismo , Transducción de Señal , Trasplante de Células Madre

RESUMEN

Creatine has been proposed to exert beneficial effects in the management of depression, but the cell signaling pathways implicated in its antidepressant effects are not well established. This study investigated the involvement of PI3K/Akt signaling pathway and its downstream intracellular targets in the antidepressant-like effect of creatine. The acute treatment of mice with creatine (1 mg/kg, po) increased the Akt and P70S6K phosphorylation, and HO-1, GPx and PSD95 immunocontents. The pretreatment of mice with LY294002 (10 nmol/mouse, icv, PI3K inhibitor), wortmannin (0.1 µg/mouse, icv, PI3K inhibitor), ZnPP (10 µg/mouse, icv, HO-1 inhibitor), or rapamycin (0.2 nmol/mouse, icv, mTOR inhibitor) prevented the antidepressant-like effect of creatine (1 mg/kg, po) in the TST. In addition, the administration of subeffective dose of either the selective GSK3 inhibitor AR-A014418 (0.01 µg/mouse, icv), the nonselective GSK3 inhibitor lithium chloride (10 mg/kg, po), or the HO-1 inductor CoPP (0.01 µg/mouse, icv), in combination with a subeffective dose of creatine (0.01 mg/kg, po) reduced the immobility time in the TST as compared with either drug alone. No treatment caused significant changes in the locomotor activity of mice. These results indicate that the antidepressant-like effect of creatine in the TST depends on the activation of Akt, Nrf2/HO-1, GPx, and mTOR, and GSK3 inhibition.

Asunto(s)

Antidepresivos/farmacología , Creatina/farmacología , Espacio Intracelular/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal , Animales , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Homólogo 4 de la Proteína Discs Large/metabolismo , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Glucógeno Sintasa Quinasa 3/antagonistas & inhibidores , Glucógeno Sintasa Quinasa 3/metabolismo , Hemo-Oxigenasa 1/metabolismo , Hipocampo/metabolismo , Masculino , Ratones , Fosforilación/efectos de los fármacos , Proteína Quinasa C/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Quinasas S6 Ribosómicas 70-kDa/metabolismo , Transducción de Señal/efectos de los fármacos , Especificidad por Sustrato/efectos de los fármacos , Serina-Treonina Quinasas TOR/metabolismo

RESUMEN

The central and peripheral nervous system is built by a network of many different neuronal phenotypes together with glial and other supporting cells. The repertoire of expressed receptors and secreted neurotransmitters and neuromodulators are unique for each single neuron leading to intracellular signaling cascades, many of them involving intracellular calcium signaling. Here we suggest the use of calcium signaling analysis upon specific agonist application to reliably identify neuronal phenotypes, being important not only for basic science, but also providing a reliable tool for functional characterization of cells prior to transplantation. Calcium imaging provides various cellular information including signaling amplitudes, cell localization, duration, and frequency. Microfluorimetry reveals a signal summarizing the entire population, and its use is indicated for high-throughput screening purposes.

Asunto(s)

Señalización del Calcio , Calcio/análisis , Fluorometría/métodos , Neurogénesis , Neuronas/citología , Animales , Calcio/metabolismo , Técnicas de Cultivo de Célula/métodos , Células Madre Embrionarias/citología , Células Madre Embrionarias/metabolismo , Humanos , Neuronas/metabolismo

RESUMEN

The modulation of N-methyl-D-aspartate receptor (NMDAR) and L-arginine/nitric oxide (NO) pathway is a therapeutic strategy for treating depression and neurologic disorders that involves excitotoxicity. Literature data have reported that creatine exhibits antidepressant and neuroprotective effects, but the implication of NMDAR and L-arginine/nitric oxide (NO) pathway in these effects is not established. This study evaluated the influence of pharmacological agents that modulate NMDAR/L-arginine-NO pathway in the anti-immobility effect of creatine in the tail suspension test (TST) in mice. The NOx levels and cellular viability in hippocampal and cerebrocortical slices of creatine-treated mice were also evaluated. The anti-immobility effect of creatine (10 mg/kg, po) in the TST was abolished by NMDA (0.1 pmol/mouse, icv), D-serine (30 µg/mouse, icv, glycine-site NMDAR agonist), arcaine (1 mg/kg, ip, polyamine site NMDAR antagonist), L-arginine (750 mg/kg, ip, NO precursor), SNAP (25 µg/mouse, icv, NO donor), L-NAME (175 mg/kg, ip, non-selective NOS inhibitor) or 7-nitroindazole (50 mg/kg, ip, neuronal NOS inhibitor), but not by DNQX (2.5 µg/mouse, icv, AMPA receptor antagonist). The combined administration of sub-effective doses of creatine (0.01 mg/kg, po) and NMDAR antagonists MK-801 (0.001 mg/kg, po) or ketamine (0.1 mg/kg, ip) reduced immobility time in the TST. Creatine (10 mg/kg, po) increased cellular viability in hippocampal and cerebrocortical slices and enhanced hippocampal and cerebrocortical NO x levels, an effect potentiated by L-arginine or SNAP and abolished by 7-nitroindazole or L-NAME. In conclusion, the anti-immobility effect of creatine in the TST involves NMDAR inhibition and enhancement of NO levels accompanied by an increase in neural viability.

Asunto(s)

Antidepresivos/farmacología , Arginina/metabolismo , Creatina/farmacología , Depresión/metabolismo , Óxido Nítrico/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Animales , Depresión/tratamiento farmacológico , Depresión/genética , Femenino , Suspensión Trasera , Humanos , Ratones , Ratas , Ratas Wistar , Receptores de N-Metil-D-Aspartato/genética , Transducción de Señal

RESUMEN

Mounting evidence suggests a chronic pro-inflammatory state in individuals with bipolar disorder (BD). Stress exposure is known to exacerbate several inflammatory conditions as well as psychiatric disorders. Here, we analyzed plasma levels of pro-inflammatory cytokines and their soluble receptors to realistic acute psychosocial stress challenge in BD. Thirteen euthymic type 1 BD patients and 15 matched controls underwent the Trier Social Stress Test protocol (TSST). Blood samples were collected before and after TSST and plasma cytokines interleukin IL-2, IL-6, IL-33, and tumor necrosis factor alpha (TNF-α) were measured. In addition TNF-α soluble receptors TNFR1 and TNFR2, and IL-33 soluble receptor sST2 were assessed. Increased IL-33 and reduced sST2 levels were observed in BD subjects as compared to controls, independently of stress exposure. Following TSST, there were higher levels of IL-2 and reduced levels of sTNFR1 in both groups. However, the magnitude change for both cytokines was found higher in controls than BD subjects. Our data suggest that BD patients have differential stress reactivity as compared to controls, possibly related to an immunologic imbalance and failure of regulatory mechanisms.

Asunto(s)

Trastorno Bipolar/metabolismo , Citocinas/metabolismo , Receptores de Superficie Celular/metabolismo , Receptores Tipo II del Factor de Necrosis Tumoral/metabolismo , Receptores Tipo I de Factores de Necrosis Tumoral/metabolismo , Estrés Psicológico/metabolismo , Adulto , Trastorno Bipolar/psicología , Estudios de Casos y Controles , Femenino , Humanos , Proteína 1 Similar al Receptor de Interleucina-1 , Persona de Mediana Edad

RESUMEN

BACKGROUND: The aim of this study was to investigate the involvement of signaling pathways on the creatine antidepressant-like effect in the tail suspension test (TST) in mice. METHODS: The TST was used to assess the antidepressant-like properties of creatine. RESULTS: The anti-immobility effect of creatine (1mg/kg, p.o.) in the TST was blocked by i.c.v. pretreatment with H-89 (1µg/site, PKA inhibitor), KN-62 (1µg/site, CAMK-II inhibitor), chelerythrine (1µg/site, PKC inhibitor), U0126 (5µg/site, MEK1/2 inhibitor) or PD09058 (5µg/site, MEK1/2 inhibitor). CONCLUSION: These results suggest that the antidepressant-like effect of creatine is dependent on PKA, CaMK-II, PKC and MEK 1/2 activation.

Asunto(s)

Antidepresivos/uso terapéutico , Creatina/uso terapéutico , Proteínas Serina-Treonina Quinasas/metabolismo , Transducción de Señal/efectos de los fármacos , Estrés Psicológico/tratamiento farmacológico , Estrés Psicológico/enzimología , Animales , Antidepresivos/administración & dosificación , Conducta Animal/efectos de los fármacos , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/metabolismo , Creatina/administración & dosificación , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Modelos Animales de Enfermedad , Suspensión Trasera , Inyecciones Intraventriculares , Masculino , Ratones , Quinasas de Proteína Quinasa Activadas por Mitógenos/metabolismo , Actividad Motora/efectos de los fármacos , Proteína Quinasa C/metabolismo , Inhibidores de Proteínas Quinasas/farmacología

RESUMEN

Ursolic acid (UA) is a natural pentacyclic triterpenoid carboxylic acid that exerts antidepressant-like effects in the tail suspension test (TST) and in the forced swimming test, and this effect was reported to be mediated by the dopaminergic system. Many studies show that currently available antidepressant agents have effects on multiple neurotransmitter systems which account for their efficacy. Therefore, this study was aimed at investigating the possible involvement of the serotonergic, noradrenergic, glutamatergic and opioid systems in the antidepressant-like effect of UA. To this end, several pharmacological agents were administered to verify their ability to influence the antidepressant-like responses elicited by UA in the TST in mice. The open-field test was used to assess the locomotor activity. The results show that the pre-treatment of mice with ρ-chlorophenylalanine (100mg/kg, i.p., 4 days) or α-methyl-ρ-tyrosine (100mg/kg, i.p.) but not with N-methyl-d-aspartate (0.1 pmol/mouse, i.c.v.) or naloxone (1mg/kg, i.p.), was able to prevent the antidepressant-like effect of UA (0.1mg/kg, p.o.). Sub-effective doses of fluoxetine (5mg/kg, p.o.) or reboxetine (2mg/kg, p.o.), but not ketamine (0.1mg/kg, i.p.) or MK-801 (0.001 mg/kg, p.o.), was capable of potentiating the effect of a sub-effective dose of UA (0.001 mg/kg, p.o.) in the TST. None of the treatments affected locomotor activity. Altogether, the results show an involvement of the serotonergic and noradrenergic systems, but not the glutamatergic or opioid systems, in the antidepressant-like effect of UA.

Asunto(s)

Antidepresivos/farmacología , Norepinefrina/fisiología , Serotonina/fisiología , Triterpenos/farmacología , Animales , Antidepresivos/administración & dosificación , Conducta Animal/efectos de los fármacos , Femenino , Inyecciones Intraventriculares , Masculino , Ratones , Triterpenos/administración & dosificación , Ácido Ursólico

RESUMEN

Bipolar disorder (BD) has been associated with immune imbalance, including lymphocyte activation and increased pro-inflammatory cytokines. Immune activation is part of stress response, and psychosocial stress has been implicated in the pathogenesis of psychiatric disorders. Here, we investigated the neuroendocrine and immune responses to acute psychosocial stress challenge in BD. Thirteen euthymic participants with type 1 BD and 15 healthy controls underwent the Trier Social Stress Test protocol (TSST). Blood samples were collected before and after TSST. Lymphocytes were isolated and stimulated in vitro to assess lymphocyte activation profile, lymphocyte sensitivity to dexamethasone, mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NF-κB) signaling by flow cytometry. Heart rate and salivary cortisol levels were monitored across the task. BD participants exhibited blunted stress responses as shown by reduced heart rate and salivary cortisol levels in comparison to healthy controls. BD was also associated with reduction in the percentage of regulatory T cells, but with expansion of activated T cells. When compared to controls, patients showed increased lymphocyte MAPK p-ERK and p-NF-κB signaling after the stress challenge, but exhibited a relative lymphocyte resistance to dexamethasone. In conclusion, stress-related neuroendocrine responses are blunted, associated with increased immune activation and lower sensitivity to glucocorticoids in BD. An inability in reducing NF-κB and MAPK signaling following TSST could be underlying the immune imbalance observed in BD.

Asunto(s)

Trastorno Bipolar/inmunología , Trastorno Bipolar/fisiopatología , Activación de Linfocitos , Sistemas Neurosecretores/fisiopatología , Estrés Psicológico/inmunología , Estrés Psicológico/fisiopatología , Adulto , Trastorno Bipolar/sangre , Femenino , Frecuencia Cardíaca/fisiología , Humanos , Hidrocortisona/análisis , Persona de Mediana Edad

RESUMEN

Creatine was previously shown to produce an antidepressant-like effect in the tail suspension test through a modulation of the dopaminergic system. In this study, the mechanisms underlying its antidepressant-like effect were further evaluated by investigating the involvement of the serotonergic system in its effect. The anti-immobility effect of creatine (1mg/kg) was prevented by the pretreatment of mice with p-chlorophenylalanine methyl ester (PCPA; 100mg/kg, i.p., for 4 consecutive days, an inhibitor of serotonin (5-HT) synthesis). Creatine (0.01 mg/kg, sub-effective dose) in combination with sub-effective doses of WAY100635 (0.1mg/kg, s.c., a 5-HT1A receptor antagonist), 8-OH-DPAT (0.1mg/kg, i.p., a 5-HT1A receptor agonist) or selective serotonin reuptake inhibitors fluoxetine (5mg/kg, p.o.), paroxetine (0.1mg/kg, p.o.), citalopram (0.1mg/kg, p.o.) and sertraline (3mg/kg, p.o.) reduced the immobility time in the tail suspension test as compared with either drug alone. These results indicate that the antidepressant-like effect of creatine is likely mediated by an interaction with 5-HT1A receptors. Of note, the present results also indicate that creatine improves the effectiveness of the selective serotonin reuptake inhibitors, a finding that may have therapeutic implications for the treatment of depressive disorders.

Asunto(s)

Antidepresivos/farmacología , Creatina/farmacología , Depresión/tratamiento farmacológico , Receptor de Serotonina 5-HT1A/metabolismo , Antagonistas del Receptor de Serotonina 5-HT1/farmacología , Animales , Trastorno Depresivo/tratamiento farmacológico , Suspensión Trasera/métodos , Humanos , Ratones , Paroxetina/metabolismo , Serotonina/metabolismo

RESUMEN

The antidepressant-like activity of creatine in the tail suspension test (TST) was demonstrated previously by our group. In this study we investigated the involvement of the noradrenergic system in the antidepressant-like effect of creatine in the mouse TST. In the first set of experiments, creatine administered by i.c.v. route (1 µg/site) decreased the immobility time in the TST, suggesting the central effect of this compound. The anti-immobility effect of peripheral administration of creatine (1 mg/kg, p.o.) was prevented by the pretreatment of mice with α-methyl-p-tyrosine (100 mg/kg, i.p., inhibitor of tyrosine hydroxylase), prazosin (1 mg/kg, i.p., α1-adrenoceptor antagonist), but not by yohimbine (1 mg/kg, i.p., α2-adrenoceptor antagonist). Creatine (0.01 mg/kg, subeffective dose) in combination with subeffective doses of amitriptyline (1 mg/kg, p.o., tricyclic antidepressant), imipramine (0.1 mg/kg, p.o., tricyclic antidepressant), reboxetine (2 mg/kg, p.o., selective noradrenaline reuptake inhibitor) or phenylephrine (0.4 µg/site, i.c.v., α1-adrenoceptor agonist) reduced the immobility time in the TST as compared with either drug alone. These results indicate that the antidepressant-like effect of creatine is likely mediated by an activation of α1-adrenoceptor and that creatine produces synergistic effects in the TST with antidepressants that modulate noradrenaline transporter, suggesting that an improvement in the response to the antidepressant therapy may occur when creatine is combined with these antidepressants. Furthermore, the synergistic effect of creatine (0.01 mg/kg, p.o.) and reboxetine (2 mg/kg, p.o.) combination was abolished by the α1-adrenoceptor antagonist prazosin, indicating that the antidepressant-like effect of combined therapy is likely mediated by an activation of α1-adrenoceptor.

Asunto(s)

Antidepresivos/uso terapéutico , Creatina/uso terapéutico , Depresión/tratamiento farmacológico , Suspensión Trasera/métodos , Receptores Adrenérgicos alfa 1/metabolismo , Adrenérgicos/farmacología , Análisis de Varianza , Animales , Depresión/diagnóstico , Modelos Animales de Enfermedad , Interacciones Farmacológicas , Inhibidores Enzimáticos/administración & dosificación , Conducta Exploratoria/efectos de los fármacos , Inyecciones Intraventriculares , Masculino , Ratones , Factores de Tiempo , alfa-Metiltirosina/administración & dosificación

RESUMEN

The aim of this study was to investigate the antidepressant-like effect of fractions from Rosmarinus officinalis L.: ethyl acetate 1 and 2 (AcOEt1 and 2), hexane (HEX), ethanolic (ET), and essential oil-free (EOF) fractions, as well as essential oil, the isolated compounds carnosol and betulinic acid in the tail suspension test, a predictive test of antidepressant activity. Swiss mice were acutely administered by oral route (p.o.) with fractions, essential oil or isolated compounds, 60 min before the tail suspension test or open-field test. All of them produced a significant antidepressant-like effect: AcOEt1, ET, EOF fractions and essential oil (0.1-100mg/kg, p.o); HEX (0.1-10mg/kg, p.o) and AcOEt2 fraction (0.1-1mg/kg, p.o), carnosol (0.01-0.1mg/kg, p.o.) isolated from the HEX fraction and betulinic acid (10mg/kg, p.o.), isolated from the AcOEt1 and AcOEt2 fractions. No psychostimulant effect was shown in the open-field test, indicating that the effects in the tail suspension test are specific. This study suggests that carnosol and betulinic acid could be responsible for the anti-immobility effect of extracts from R. officinalis.

Asunto(s)

Abietanos/administración & dosificación , Antidepresivos/administración & dosificación , Depresión/tratamiento farmacológico , Aceites Volátiles/administración & dosificación , Extractos Vegetales/administración & dosificación , Rosmarinus/química , Triterpenos/administración & dosificación , Abietanos/análisis , Abietanos/aislamiento & purificación , Animales , Antidepresivos/química , Antidepresivos/aislamiento & purificación , Depresión/psicología , Suspensión Trasera , Humanos , Masculino , Ratones , Aceites Volátiles/química , Aceites Volátiles/aislamiento & purificación , Triterpenos Pentacíclicos , Extractos Vegetales/aislamiento & purificación , Triterpenos/análisis , Triterpenos/aislamiento & purificación , Ácido Betulínico

RESUMEN

PURPOSE: Physical activity is currently being considered an effective alternative in the treatment of depression. At the preclinical level, the voluntary running wheel is a useful method of increasing physical activity in rodents and induces an antidepressant-like effect in some behavioral paradigms. METHODS: This study investigated the effect of physical activity on a voluntary running wheel in mice submitted to the forced swimming test (FST) and tail suspension test, two predictive tests of antidepressant properties. Moreover, the influence of the inhibition of serotonin and noradrenaline synthesis as well as the inhibition of protein kinase A (PKA) and calcium/calmodulin-dependent protein kinase II (CAMK-II) activity by pharmacological agents in the antidepressant-like action of physical activity was investigated. RESULTS: Physical activity on a voluntary running wheel by 21 d produced a reduction in the immobility time in the FST and tail suspension test, without producing alteration on locomotor activity in the open-field test. The antidepressant-like effect in the FST elicited by physical activity lasted for 7 d after removal of the running wheel. The anti-immobility effect of physical activity was prevented by the pretreatment of mice with p-chlorophenylalanine methyl ester (100 mg·kg, i.p., once a day, for four consecutive days, inhibitor of serotonin synthesis), α-methyl-p-tyrosine (100 mg·kg, i.p., an inhibitor of noradrenaline and dopamine synthesis), H-89 (1 µg per site, i.c.v., a PKA inhibitor), and KN-62 (1 µg per site, i.c.v., a CAMK-II inhibitor). CONCLUSIONS: Taken together, these results first suggest that the effect of physical activity on the FST is dependent on either the increase in the bioavailability of monoamines in the synaptic cleft or an activation of intracellular signaling pathways mediated by PKA and CAMK-II.

Asunto(s)

Condicionamiento Físico Animal/psicología , 1-(5-Isoquinolinesulfonil)-2-Metilpiperazina/análogos & derivados , 1-(5-Isoquinolinesulfonil)-2-Metilpiperazina/farmacología , Animales , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/fisiología , Suspensión Trasera , Isoquinolinas/farmacología , Masculino , Ratones , Inhibidores de Proteínas Quinasas/farmacología , Sulfonamidas/farmacología