RESUMO
Sepsis-associated encephalopathy (SAE) is a significant problem in patients with sepsis, and it is associated with a decrease in cognitive and sensitivity capability induced by systemic inflammation. SAE is implicated in reversible brain damage of several regions related to cognition, emotion, and sensation; however, it is not well established if it could affect brain regions associated with nociceptive modulation. Here were evaluated the nociceptive thresholds in rats with systemic inflammation induced by cecal ligation puncture (CLP). After 24 h of CLP, it was observed an increase in nociceptive threshold in all tests. Periaqueductal gray, rostroventral medulla, critical regions for descending nociceptive modulation, were evaluated and showed enhanced pro-inflammatory cytokines as well as glial activation. These results suggest that systemic inflammation could compromise descending facilitatory pathways, impairing nociceptive sensory functioning.
RESUMO
BACKGROUND/PURPOSE: During the early phase of sepsis, hypotension is accompanied by increase of plasma vasopressin hormone (AVP) levels, which decline during the late phase. This hypotension is due in part to increase of nitric oxide (NO) synthesis by nitric oxide synthase (NOS) enzyme. Neuronal isoform of this enzyme (nNOS) is present in vasopressinergics neurons of hypothalamus, but its role in vasopressin secretion during sepsis is unknown. METHODS: We evaluated the role of nNOS in NO production and vasopressin secretion during sepsis. Wistar rats received 7-nitroindazole (50 mg/kg, i.p.), an inhibitor of nNOS activity, or vehicle and were submitted to septic stimulus by cecal ligation and puncture (CLP). At the time points 0, 4, 6, 18 and 24 h after sepsis induction the animals were decapitated and neurohypophysis and hypothalamus were removed for analysis of vasopressin content and NOS activity, respectively. Hematocrit, serum sodium, osmolality, proteins and plasmatic AVP were quantified. RESULTS: Mortality was not affected by 7-nitroindazole (7-NI). Sodium and plasma proteins levels decreased after CLP and the treatment anticipated the protein loss, and delayed serum sodium decrease. Septic animals treated with 7-NI showed decrease of osmolality 4 h after CLP. Nitric oxide synthase activity in hypothalamus increased at 4 and 24 h after CLP and was reduced with 7-NI. Neurohypophysis content of AVP diminished after CLP and 7-NI did not alter this parameter. Plasma AVP levels increased at 6 h and decreased 18 and 24 h after CLP. Treatment with 7-NI did not alter plasma vasopressin levels. CONCLUSION: We concluded that nNOS does not have a substantial role in vasopressin secretion during experimental sepsis.
Assuntos
Arginina Vasopressina/metabolismo , Óxido Nítrico Sintase Tipo I/metabolismo , Sepse/metabolismo , Vasopressinas/metabolismo , Animais , Masculino , Óxido Nítrico/metabolismo , Radioimunoensaio , Ratos , Ratos WistarRESUMO
Previous studies have shown that in the early phase of sepsis, the plasma concentration of arginine vasopressin (AVP) is increased, but in the late phase, its levels remain inadequately low, despite of persistent hypotension. One hypothesis suggested for this relative deficiency is apoptosis of vasopressinergic neurons. Here, we investigated apoptosis pathways in the hypothalamus during sepsis, as well as mechanisms underlying this process. Male Wistar rats were submitted to sepsis by cecal ligation and puncture (CLP) or nonmanipulated (naive) as control. After 6 and 24 h, the animals were decapitated and brain and blood were collected to assess hypothalamic apoptotic markers, IFN-γ plasma levels, and evidence for breakdown of the blood-brain barrier (BBB). Sepsis caused a decrease in mitochondrial antiapoptotic proteins (Bcl-2, Bcl-xL) in the hypothalamus, but had no effect on markers of cell death mediated by death receptors or immune cells. In the supraoptic nuclei of these animals, microglia morphology was consistent with activation, associated with an increase in plasma IFN-γ. A transitory breakdown of BBB in the hypothalamus was seen at 6 h following CLP. The results indicate that the intrinsic but not extrinsic apoptosis pathway is involved in the cell death observed in vasopressinergic neurons, and that this condition is temporally associated with microglial activation and BBB leaking.
Assuntos
Apoptose/fisiologia , Arginina Vasopressina/metabolismo , Hipotálamo/metabolismo , Neurônios/metabolismo , Sepse/metabolismo , Animais , Barreira Hematoencefálica/metabolismo , Hipotálamo/efeitos dos fármacos , Masculino , Óxido Nítrico/metabolismo , Ratos WistarRESUMO
Previous studies revealed the presence of LTC(4) synthase in paraventricular vasopressinergic neurons, suggesting a role for leukotrienes (LTs) in certain neuroendocrine system functions. Our aim was to study the effect of an inhibitor of LT synthesis in the release of arginine vasopressin (AVP) following an osmotic stimulus in rats. Male Wistar rats received an intra-cerebroventricular injection of 2 µl of the LT synthesis inhibitor MK-886 (1, 2, or 4 µg/kg), or vehicle (DMSO 5%), 1h before an intraperitoneal injection of hypertonic saline (NaCl 2M) or isotonic saline (NaCl 0.01 M) in a volume corresponding to 1% of body weight. Thirty minutes after the osmotic stimulus, the animals were decapitated and blood was collected for determining hematocrit, plasma osmolality and plasma AVP levels. As expected, the injection of hypertonic saline significantly increased (P<0.05) the hematocrit, plasma osmolality and plasma AVP levels. While inhibiting LT synthesis by central administration of MK-886 did not cause any additional increase in hematocrit or osmolality, plasma AVP levels were augmented (P<0.05). We conclude that central leukotrienes may have a modulatory role in AVP secretion following an osmotic stimulus, this deserving future studies.
Assuntos
Arginina Vasopressina/metabolismo , Glutationa Transferase/metabolismo , Indóis/farmacologia , Antagonistas de Leucotrienos/farmacologia , Leucotrienos/biossíntese , Inibidores da Proteína Ativadora de 5-Lipoxigenase/farmacologia , Proteínas Ativadoras de 5-Lipoxigenase/metabolismo , Animais , Arginina Vasopressina/sangue , Peso Corporal , Glutationa Transferase/antagonistas & inibidores , Hematócrito , Indóis/administração & dosagem , Antagonistas de Leucotrienos/administração & dosagem , Leucotrienos/metabolismo , Masculino , Neurônios/efeitos dos fármacos , Neurônios/enzimologia , Neurônios/metabolismo , Concentração Osmolar , Radioimunoensaio , Ratos , Ratos Wistar , Solução Salina Hipertônica/administração & dosagem , Solução Salina Hipertônica/farmacologia , Cloreto de Sódio/administração & dosagemRESUMO
OBJECTIVE: To determine if the magnitude of the force used to induce incisor tooth movement promotes distinct activation in cells in the central amygdala (CEA) and lateral hypothalamus (LH) of rats. Also, the effect of morphine on Fos immunoreactivity (Fos-IR) was investigated in these nuclei. MATERIALS AND METHODS: Adult male rats were anesthetized and divided into six groups: only anesthetized (control), without orthodontic appliance (OA), OA but without force, OA activated with 30g or 70g, OA with 70g in animals pretreated with morphine (2 mg/kg, intraperitoneal). Three hours after the onset of the experiment the rats were reanesthetized and perfused with 4% paraformaldehyde. The brains were removed and fixed, and sections containing CEA and LH were processed for Fos protein immunohistochemistry. RESULTS: The results show that in the control group, the intramuscular injection of a ketamine/ xylazine mixture did not induce Fos-IR cells in the CEA or in the LH. Again, the without force group showed a little Fos-IR. However, in the 70g group the Fos-IR was the biggest observed (P < .05, Tukey) in the CEA and LH compared with the other groups. In the 30g group, the Fos-IR did not differ from the control group, the without OA group, and the without force group. Furthermore, pretreatment with morphine in the 70g group reduced Fos-IR in these regions. CONCLUSIONS: Tooth movement promotes Fos-IR in the CEA and LH according to the magnitude of the force applied.
Assuntos
Tonsila do Cerebelo/fisiologia , Região Hipotalâmica Lateral/fisiologia , Técnicas de Movimentação Dentária , Tonsila do Cerebelo/efeitos dos fármacos , Tonsila do Cerebelo/patologia , Animais , Fenômenos Biomecânicos , Região Hipotalâmica Lateral/efeitos dos fármacos , Região Hipotalâmica Lateral/patologia , Processamento de Imagem Assistida por Computador , Imuno-Histoquímica , Incisivo/patologia , Injeções Intraperitoneais , Masculino , Morfina/administração & dosagem , Morfina/farmacologia , Entorpecentes/administração & dosagem , Entorpecentes/farmacologia , Vias Neurais/efeitos dos fármacos , Vias Neurais/fisiologia , Neurônios/efeitos dos fármacos , Neurônios/patologia , Neurônios/fisiologia , Nociceptores/efeitos dos fármacos , Nociceptores/fisiologia , Proteínas Oncogênicas v-fos/análise , Proteínas Oncogênicas v-fos/efeitos dos fármacos , Braquetes Ortodônticos , Fios Ortodônticos , Ratos , Ratos Wistar , Estresse Mecânico , Técnicas de Movimentação Dentária/instrumentaçãoRESUMO
This study examined whether electrolytic ablation of the periventricular anteroventral third ventricle (AV3V) region would affect the hypothalamic activation and the increase of hypophysial hormone secretion induced by systemic injection of lipopolysaccharide (LPS) in rats. LPS significantly increased the number of cells showing Fos immunoreactivity in the paraventricular (PVN) and supraoptic (SON) nuclei of the hypothalamus (P<0.05) and also increased plasma levels of vasopressin, oxytocin, adrenocorticotropin and corticosterone (P<0.05). AV3V lesion significantly reduced LPS-induced Fos immunoreactivity (P<0.05) and vasopressin and oxytocin secretion (P<0.05). Elevations in adrenocorticotropin but not in plasma corticosterone after LPS were affected by prior AV3V lesions. These findings demonstrate that LPS-induced Fos expression in the PVN and SON, and hypophysial hormone secretion is dependent on the integrity of the AV3V region.
Assuntos
Sistema Hipotálamo-Hipofisário/metabolismo , Hipotálamo/metabolismo , Hipotálamo/fisiologia , Hormônios Hipofisários/metabolismo , Terceiro Ventrículo/fisiologia , Hormônio Adrenocorticotrópico/metabolismo , Animais , Fenômenos Fisiológicos Cardiovasculares , Modelos Animais de Doenças , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Hipotálamo/anatomia & histologia , Hipotálamo/efeitos dos fármacos , Mediadores da Inflamação/farmacologia , Lipopolissacarídeos/farmacologia , Masculino , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Ocitocina/metabolismo , Núcleo Hipotalâmico Paraventricular/efeitos dos fármacos , Núcleo Hipotalâmico Paraventricular/metabolismo , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos , Ratos Wistar , Choque Séptico/metabolismo , Choque Séptico/fisiopatologia , Estresse Fisiológico/metabolismo , Estresse Fisiológico/fisiopatologia , Núcleo Supraóptico/efeitos dos fármacos , Núcleo Supraóptico/metabolismo , Terceiro Ventrículo/anatomia & histologia , Vasopressinas/metabolismo , Equilíbrio Hidroeletrolítico/fisiologiaRESUMO
During the early phase of endotoxic shock the hypothalamus is activated and neurohypophyseal hormone secretion is increased. In order to study the participation of the subfornical organ (SFO) in this response we lesioned the nucleus and determined hormone secretion and c-fos expression in the paraventricular and supraoptic nuclei after administration of lipopolysaccharides (LPS) in rats. LPS significantly increased the number of cells showing Fos immunoreactivity in the paraventricular and supraoptic nuclei of the hypothalamus (p < 0.05) and also caused an increase in plasma levels of vasopressin and oxytocin (p < 0.05). SFO lesion significantly reduced LPS-induced Fos immunoreactivity (p < 0.05) and hormone secretion (p < 0.05). We conclude that the SFO participates in the activation of the hypothalamic-neurohypophyseal axis in the early phase of endotoxic shock.
Assuntos
Hipotálamo/fisiopatologia , Neuro-Hipófise/fisiopatologia , Choque Séptico/fisiopatologia , Animais , Modelos Animais de Doenças , Hipotálamo/patologia , Masculino , Neuro-Hipófise/patologia , Ratos , Ratos Wistar , Choque Séptico/patologiaRESUMO
Lipopolysaccharides (LPS) can be used to induce experimental endotoxic shock, which is characterized by a significant decrease in mean arterial pressure (MAP) and a decreased vasoconstrictor response that have been attributed to excessive nitric oxide production. Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase), in addition to lowering serum cholesterol levels, exert many pleiotropic effects, including anti-inflammatory action. In the present study, we investigated the effect of simvastatin, an HMG-CoA reductase inhibitor, on the production of nitric oxide and the cardiovascular response to LPS. Male Wistar rats were pretreated with different doses of simvastatin (10, 20, 40, and 80 mg/kg, i.p.) or saline 20 min before i.v. injection of LPS (1.5 mg/kg) or saline (control). MAP was continuously recorded and nitrate plasma concentration was determined during the 6-h experimental session at 1-h intervals. The pressor response to phenylephrine (1 microg/kg) was evaluated before and 6 h after LPS administration. In the LPS-treated group, there was a time-dependent increase in nitrate plasma concentration (P<0.001), and this response was decreased in simvastatin pretreated rats (P<0.001). We also observed that LPS decreased the pressor response to phenylephrine (P<0.001), an effect that was reverted by simvastatin pretreatment (P<0.05). However, simvastatin did not modify the decrease of MAP induced by LPS. We concluded that simvastatin decreases nitrate plasma concentration in response to LPS and recovers vascular responsiveness during an experimental endotoxic shock. These data suggest the potential use of HMG-CoA reductase inhibitors as a coadjuvant in the treatment of septic shock.