Assuntos
Serotonina , Dor Visceral , Animais , Camundongos , Receptores 5-HT3 de Serotonina , Bexiga UrináriaRESUMO
The injection of repeated doses of lipopolysaccharide (LPS) results in attenuation of the immune response, which is an important mechanism to prevent deleterious long-term excessive inflammation. Brain-mediated mechanisms are involved in this endogenous anti-inflammatory effect, but nothing is known about the putative role of the splenic anti-inflammatory reflex (which has recently been described as a powerful mechanism involved in the suppression of immune response) during immune tolerance. Therefore, we tested the hypothesis that endotoxin tolerance is at least in part mediated by the splenic anti-inflammatory reflex. Body core temperature (Tb) was measured in rats previously submitted to splenectomy. Immune tolerance was induced by means of five consecutive LPS (100⯵g/kg) intraperitoneal injections at 24-h intervals. In sham operated rats, we observed a significant reduction of the febrile response to repeated administration of LPS, which was not altered in rats submitted to splenectomy. Moreover, plasma pro-inflammatory cytokines [tumor necrosis factor-α (TNF-α), interleukin (IL)-1ß and IL-6] and prostaglanding E2 (PGE2) surges besides preoptic PGE2 levels were observed after the first LPS administration but not in tolerant animals, and this pattern was kept the same in splenectomized rats. These data are consistent with the notion that the splenic anti-inflammatory reflex does not modulate immune tolerance in rats.
Assuntos
Tolerância Imunológica , Baço/imunologia , Animais , Temperatura Corporal , Citocinas/sangue , Dinoprostona/sangue , Lipopolissacarídeos/farmacologia , Masculino , Ratos Wistar , Baço/efeitos dos fármacos , Baço/cirurgia , EsplenectomiaRESUMO
BACKGROUND: Lipopolysaccharide (LPS)-induced systemic inflammation (SI) is associated with neuroinflammation in the brain, hypotension, tachycardia, and multiple organs dysfunctions. Considering that during SI these important cardiovascular and inflammatory changes take place, we measured the sensitivity of the cardiovascular reflexes baroreflex, chemoreflex, and Bezold-Jarisch that are key regulators of hemodynamic function. We also evaluated neuroinflammation in the nucleus tractus solitarius (NTS), the first synaptic station that integrates peripheral signals arising from the cardiovascular and inflammatory status. METHODS: We combined cardiovascular recordings, immunofluorescence, and assays of inflammatory markers in male Wistar rats that receive iv administration of LPS (1.5 or 2.5 mg kg-1) to investigate putative interactions of the neuroinflammation in the NTS and in the anteroventral preoptic region of the hypothalamus (AVPO) with the short-term regulation of blood pressure and heart rate. RESULTS: LPS induced hypotension, tachycardia, autonomic disbalance, hypothermia followed by fever, and reduction in spontaneous baroreflex gain. On the other hand, during SI, the bradycardic component of Bezold-Jarisch and chemoreflex activation was increased. These changes were associated with a higher number of activated microglia and interleukin (IL)-1ß levels in the NTS. CONCLUSIONS: The present data are consistent with the notion that during SI and neuroinflammation in the NTS, rats have a reduced baroreflex gain, combined with an enhancement of the bradycardic component of Bezold-Jarisch and chemoreflex despite the important cardiovascular impairments (hypotension and tachycardia). These changes in the cardiac component of Bezold-Jarisch and chemoreflex may be beneficial during SI and indicate that the improvement of theses reflexes responsiveness though specific nerve stimulations may be useful in the management of sepsis.
Assuntos
Hemodinâmica/fisiologia , Inflamação/fisiopatologia , Núcleo Solitário/fisiopatologia , Animais , Hemodinâmica/efeitos dos fármacos , Inflamação/induzido quimicamente , Lipopolissacarídeos/toxicidade , Masculino , Ratos , Ratos Wistar , Núcleo Solitário/efeitos dos fármacosRESUMO
Objective: Animal models of chronic pain have demonstrated that glial cells are promising target for development of analgesic drugs. However, preclinical studies on glial response under chronic pain conditions vary depending on the cellular markers, the species used, the experimental design and model. Therefore, we investigate the expression profile of GFAP and Iba-1 during the behavioral manifestation of sensory disorder in inflammatory and neuropathic pain models. Methods: the expression profile of fibrillary acidic protein (GFAP) and ionized calcium binding adaptor molecule-1 (Iba-1) were quantitated in the spinal dorsal horn of Balb/C mice submitted to six models of chronic pain. Protein analysis was performed by western blot and the results colligated with pain-related behavior. Results: Using the same method to quantitate proteins we observed that while GFAP is upregulated after axotomy, partial nerve injury and cutaneous inflammation, its expression is not changed during muscle inflammation, non-inflammatory muscle pain, and in a viral-associated pain. Differently, Iba-1 is downregulated after axotomy but upregulated after partial lesion of peripheral nerve as well as after virus inoculation and during non-inflammatory muscle pain. Cutaneous and muscle inflammation induced no change in Iba-1 expression in the dorsal horn.In spite of a marked time-dependent variation in protein expression, mechanical allodynia was present at any time of all the models investigated. Discussion: Under distinct pain conditions, GFAP and Iba-1 expression is dependent on the origin of the stimulus, disease progression and tissue affected. Moreover, their expression and is not necessarily associated to the behavior manifestation of pain.
Assuntos
Proteínas de Ligação ao Cálcio/biossíntese , Dor Crônica/metabolismo , Proteína Glial Fibrilar Ácida/biossíntese , Inflamação/metabolismo , Proteínas dos Microfilamentos/biossíntese , Neuralgia/metabolismo , Corno Dorsal da Medula Espinal/metabolismo , Animais , Modelos Animais de Doenças , Regulação para Baixo , Inflamação/complicações , Inflamação/fisiopatologia , Masculino , Camundongos , Músculos/fisiopatologia , Nervo Isquiático/lesões , Pele/fisiopatologia , Regulação para CimaRESUMO
An exceptionally high mortality rate is observed in sepsis and septic shock. Systemic administration of lipopolysaccharide (LPS) has been used as an experimental model for sepsis resulting in an exacerbated immune response, brain neurochemistry adjustments, hypotension, and hypothermia followed by fever. Central serotonergic pathways not only modulate systemic inflammation (SI) but also are affected by SI, including in the anteroventral region of the hypothalamus (AVPO), which is the hierarchically most important region for body temperature (Tb) control. In this study, we sought to determine if central serotonin (5-HT) plays a role in SI induced by intravenous administration of LPS (1.5â¯mg/kg) in male Wistar rats (280-350â¯g) by assessing 5-HT levels in the AVPO, mean arterial pressure, heart rate, and Tb up to 300â¯min after LPS administration, as well as assessing plasma and spleen cytokine levels, nitric oxide (NO) plasma levels, and prostaglandin (PG) E2 levels in the AVPO at 75â¯min and 300â¯min after LPS administration. We observed reduced AVPO 5-HT levels, hypotension, tachycardia, hypothermia followed by fever, as well as observing increased plasma NO, plasma and spleen cytokines and AVPO PGE2 levels in SI. Intracerebroventricular (icv) administration of 5-HT 30â¯min before LPS administration prevented hypotension and hypothermia, which were accompanied by reduced plasma NO, as well as plasma TNF-α, IL-1ß, IL-6, and IL-10 and spleen TNF-α and IL-10 levels. We suggest that SI reduced 5-HT levels in the AVPO favor an increased pro-inflammatory status both centrally and peripherally that converge to hypotension and hypothermia. Moreover, our results are consistent with the notion that exogenous 5-HT given icv prevents hypotension and hypothermia probably activating the splenic anti-inflammatory pathway.
Assuntos
Citocinas/sangue , Hipotensão/metabolismo , Hipotermia/metabolismo , Inflamação/metabolismo , Serotonina/metabolismo , Baço/metabolismo , Animais , Dopamina/metabolismo , Hipotensão/complicações , Hipotálamo Anterior/metabolismo , Hipotermia/complicações , Inflamação/induzido quimicamente , Inflamação/complicações , Mediadores da Inflamação/metabolismo , Lipopolissacarídeos/administração & dosagem , Masculino , Óxido Nítrico/sangue , Norepinefrina/metabolismo , Ratos Wistar , Serotonina/administração & dosagemRESUMO
Physical exercise induces inflammatory and oxidative markers production in the skeletal muscle and this process is under the control of both endogenous and exogenous modulators. Recently, molecular hydrogen (H2) has been described as a therapeutic gas able to reduced oxidative stress in a number of conditions. However, nothing is known about its putative role in the inflammatory and oxidative status during a session of acute physical exercise in sedentary rats. Therefore, we tested the hypothesis that H2 attenuates both inflammation and oxidative stress induced by acute physical exercise. Rats ran at 80% of their maximum running velocity on a closed treadmill inhaling either the H2 gas (2% H2, 21% O2, balanced with N2) or the control gas (0% H2, 21% O2, balanced with N2) and were euthanized immediately or 3â¯h after exercise. We assessed plasma levels of inflammatory cytokines [tumor necrosis factor-α (TNF-α), interleukin (IL)-1ß and IL-6] and oxidative markers [superoxide dismutase (SOD), thiobarbituric acid reactive species (TBARS) and nitrite/nitrate (NOx)]. In addition, we evaluated the phosphorylation status of intracellular signaling proteins [glycogen synthase kinase type 3 (GSK3α/ß) and the cAMP responsive element binding protein (CREB)] that modulate several processes in the skeletal muscle during exercise, including changes in exercise-induced reactive oxygen species (ROS) production. As expected, physical exercise increased virtually all the analyzed parameters. In the running rats, H2 blunted exercise-induced plasma inflammatory cytokines (TNF-α and IL-6) surges. Regarding the oxidative stress markers, H2 caused further increases in exercise-induced SOD activity and attenuated the exercise-induced increases in TBARS 3â¯h after exercise. Moreover, GSK3α/ß phosphorylation was not affected by exercise or H2 inhalation. Otherwise, exercise caused an increased CREB phosphorylation which was attenuated by H2. These data are consistent with the notion that H2 plays a key role in decreasing exercise-induced inflammation, oxidative stress, and cellular stress.
Assuntos
Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Hidrogênio/farmacologia , Músculo Esquelético/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/antagonistas & inibidores , Administração por Inalação , Animais , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/sangue , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Glicogênio Sintase Quinase 3 beta/sangue , Glicogênio Sintase Quinase 3 beta/genética , Interleucina-1beta/antagonistas & inibidores , Interleucina-1beta/sangue , Interleucina-1beta/genética , Interleucina-6/antagonistas & inibidores , Interleucina-6/sangue , Interleucina-6/genética , Isoenzimas/sangue , Isoenzimas/genética , Masculino , Músculo Esquelético/metabolismo , Músculo Esquelético/fisiopatologia , Nitratos/antagonistas & inibidores , Nitratos/sangue , Nitritos/antagonistas & inibidores , Nitritos/sangue , Condicionamento Físico Animal/métodos , Esforço Físico/efeitos dos fármacos , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/sangue , Corrida , Superóxido Dismutase/sangue , Superóxido Dismutase/genética , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismo , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/sangue , Fator de Necrose Tumoral alfa/genéticaRESUMO
Fractalkine (FKN; CX3CL1) belongs to gamma-chemokine family and binds to CX3CR1 receptors. Currently, the mechanisms involving FKN-induced inflammatory mediators are research targets in an attempt to study immune diseases mechanisms. Besides, FKN seems to modulate inflammation in the nervous system by inducing the secretion of pro-inflammatory mediators such as prostaglandin E2 (PGE2). PGE2 is a classic and important mediator of fever that activates warm-responsive neurons in the anteroventral preoptic region of the hypothalamus (AVPO). Here, we tested the hypothesis that central FKN modulates febrigenic signaling both centrally and peripherally. We performed intracerebroventricular (icv) microinjections of saline (1⯵L) or FKN (doses of 5, 50, 500â¯pg/µL) in rats and measured body temperature (Tb) besides assessing tail skin temperature (Tsk) as a thermoeffector indicator used to calculate the heat loss index (HLI). We also measured the time course changes in AVPO PGE2, besides plasma corticosterone (CORT) and interleukin-6 (IL-6) levels. FKN induced a long lasting febrile response in which the highest dose (500â¯pg/µL) induced a marked rise on Tb that was accompanied by a reduced Tsk and HLI, consequently. FKN increased AVPO PGE2 production in a time-dependent manner besides increasing plasma CORT and IL-6 levels. Our data consistently indicate that FKN increases AVPO PGE2 production and Tb, accompanied by raised plasma IL-6 levels and activation of the hypothalamus-pituitary-adrenal axis.
Assuntos
Quimiocina CX3CL1/administração & dosagem , Dinoprostona/metabolismo , Fatores Imunológicos/administração & dosagem , Animais , Temperatura Corporal/efeitos dos fármacos , Temperatura Corporal/fisiologia , Quimiocina CX3CL1/metabolismo , Corticosterona/sangue , Relação Dose-Resposta a Droga , Febre/induzido quimicamente , Febre/imunologia , Infusões Intraventriculares , Interleucina-6/sangue , Masculino , Neuroimunomodulação , Ratos WistarRESUMO
Serotonin (5-HT) is a neuromodulator involved in several central-mediated mechanisms, such as endocrine processes, behavior, and sleep. Dysfunction of the serotonergic system is mainly linked to psychiatric disorders, but emerging evidence suggests that immune system activation may also alter brain 5-HT signaling. However, whether central 5-HT modulates systemic inflammation (SI) remains unknown. For this purpose, male Wistar rats (280-350g, 8-9weeks) were submitted to the experimental protocols beginning between 9 and 10AM with the performance of injections. The animals were housed at controlled conditions [temperature (25±1°C), light (06:00-18:00) and humidity (60-65%)]. Thus, we measured 5-HT and its metabolite 5-hydroxyindole-3-acetic acid (5-HIAA) in the anteroventral preoptic region [(AVPO) - the hierarchically most important region for body temperature (Tb) control] during lipopolysaccharide (LPS)-induced SI. We also combined LPS (100µg/kg) treatment with intracerebroventricular (icv) injection of 5-HT (5, 10 and 40µg/µL) and measured Tb ("hallmark" of SI), AVPO prostaglandin E2 [(PGE2) - an essential mediator of fever] and prostaglandin D2 [(PGD2) - a cryogenic mediator], plasma corticosterone [(CORT) - a stress marker with an endogenous anti-inflammatory effect] and interleukin-6 [(IL-6) - an immune mediator] levels. Detection limits of PGE2, PGD2, CORT and IL-6 assays were 39.1-2500pg/mL, 19.5-2500pg/mL, 0.12-2000µg/dL, and 0.125-8ng/mL, respectively. We also assessed tail skin temperature [used to calculate heat loss index (HLI)] to assess a key thermoeffector mechanism. As expected we observed LPS-induced increases in Tb, AVPO PGE2 (whereas PGD2 remained unchanged), plasma CORT and IL-6 levels, as well as a decrease in HLI. These changes were accompanied by reduced levels of AVPO 5-HT and 5-HIAA. Furthermore, we also observed a negative correlation between 5-HT and plasma CORT levels. Moreover, icv 5-HT (5, 10 and 40µg/µL) microinjection caused a U-shaped dose-response curve in LPS fever, in which the intermediate dose reduced the febrile response. Icv 5-HT (10µg/µL) microinjection prevented the LPS-induced increases in AVPO PGE2 (whereas not altering PGD2), plasma CORT and IL-6 levels, as well as preventing reduced HLI. Our data are consistent with the notion that AVPO 5-HT synthesis is down-regulated during SI, favoring AVPO PGE2 synthesis and consequently potentiating the immune response. These results reveal a novel effect of central 5-HT as an anti-inflammatory neuromodulator that may take place during psychiatric disorder treatment with 5-HT reuptake inhibitors as well as suggesting that 5-HT modulation per se is a potential therapeutic approach for inflammatory diseases.
Assuntos
Inflamação/metabolismo , Área Pré-Óptica/metabolismo , Serotonina/metabolismo , Animais , Corticosterona/sangue , Dinoprostona/metabolismo , Febre/metabolismo , Ácido Hidroxi-Indolacético/metabolismo , Inflamação/induzido quimicamente , Lipopolissacarídeos/administração & dosagem , Masculino , Prostaglandina D2/metabolismo , Ratos Wistar , Serotonina/administração & dosagem , Temperatura CutâneaRESUMO
Citral is a mixture of the two monoterpenoid isomers (neral and geranial) widely used as a health-promoting food additive safe for human and animal (approved by the US Food and Drug Administration). In vitro studies have reported on the capability of citral to reduce inflammation. Here, we report antipyretic effects of citral in vivo using the most well-accepted model of sickness syndrome, i.e., systemic administration of lipopolysaccharide ( LPS ) to rats. Citral given by gavage caused no change in control euthermic rats (treated with saline) but blunted most of the assessed parameters related to the sickness syndrome [fever (hallmark of infection), plasma cytokines (IL-1ß, IL-6, and TNF-α) release, and prostaglandin E2 (PGE2) synthesis (both peripherally and hypothalamic)]. Moreover, LPS caused a sharp increase in plasma corticosterone levels that was unaltered by citral. These data are consistent with the notion that citral has a corticosterone-independent potent antipyretic effect, acting on the peripheral febrigenic signaling (plasma levels of IL-1ß, IL-6, TNF-α, and PGE2), eventually down-modulating hypothalamic PGE2 production.
Assuntos
Antipiréticos/farmacologia , Monoterpenos/farmacologia , Monoterpenos Acíclicos , Animais , Antipiréticos/uso terapêutico , Citocinas/sangue , Dinoprostona/biossíntese , Febre/tratamento farmacológico , Inflamação/prevenção & controle , Lipopolissacarídeos , Monoterpenos/uso terapêutico , RatosRESUMO
Objetivo: avaliar a qualidade de vida (QV), sintomas depressivos e adesão ao tratamento de pessoas com Hipertensão Arterial Sistêmica (HAS). Metodologia: estudo do tipo descritivo exploratório, de corte transversal e abordagem quantitativa, realizado com a população de 155 usuários. Foram utilizados quatro instrumentos para a coleta de dados: um para caracterização sóciodemográfica e clínica, o Medical Outcomes Study 36 (SF-36), o Inventário de Depressão de Beck (BDI) e a Medida de Adesão aos Tratamentos (MTA). Os dados foram analisados segundo testes estatísticos e regressão linear simples. Resultados: o domínio mais comprometido da QV foi Aspecto físico (Média = 49,0); 34,8% apresentaram disforia, e 14,2% depressão moderada; 76,8% aderiam ao tratamento. Conclusão: as atividades avaliadas no domínio Aspecto físico da QV foram as mais comprometidas. A maioria dos sujeitos apresentou alteração psicológica e aderiu ao tratamento medicamentoso.
Objective: to evaluate the quality of life (QOL), depressive symptoms and adherence to treatment of people with Hypertension. Methodology: the study type is descriptive exploratory, cross-sectional and quantitative approach, with a total of 155 user as a target population. For data collection, four instruments were used: one for sociodemographic and clinical characterization, the Medical Outcomes Study 36 (SF-36), the Beck Depression Inventory (BDI) and the Measurement of Treatment Adherence (MTA). Data analyzes was performed with statistic tests and linear regression. Results: the most compromised domain of QOL was physical aspect (mean = 49.0); 34.8% of subjects had dysphoria, and 14.2% moderate depression; 76.8% had adhered to treatment. Conclusion: the activities evaluated in the physical domain of QOL were the most compromised. Most of subjects showed psychological change and adhere to drug treatment.
Objetivo: evaluar la calidad de vida (CV), síntomas depresivos y la adherencia al tratamiento de las personas con hipertensión arterial sistêmica (HAS). Metodología: estudio exploratorio descriptivo, transversal y de enfoque cuantitativo, realizado con 155 usuarios. Se utilizaron cuatro instrumentos para la recolección de datos: un para la caracterización sociodemográfica y clínica, el Medical Outcomes Study 36 (SF-36), el Inventario de Depresión de Beck (BDI) y la Medición de la adherencia al tratamiento (MTA). Para analisis de los datos se realizaron testes estadísticos y análisis de regresión lineal. Resultados: La zona más afectada de la CV fue el aspecto físico (media = 49,0); 34.8% tenían disforia, y el 14,2% depresión moderada; 76,8% adhiere al tratamiento. Conclusión: las actividades evaluadas en el dominio de aspecto físico de CV son los más comprometida. La mayoría mostró cambio psicológico y se adhieren al tratamiento farmacológico.