RESUMEN
Inflammation is involved in the induction of chronic inflammatory and neuropathic pain. Moreover, the ketogenic diet, a high-fat, low-carbohydrate, and adequate protein diet, has an anti-inflammatory effect. Thus, we hypothesized that a ketogenic diet has a therapeutic effect on both types of chronic pain. In the present study, we investigated the effect of a ketogenic diet on mechanical allodynia, a chronic pain symptom, in formalin-induced chronic inflammatory pain and nerve injury-induced neuropathic pain models using adult male mice. Formalin injection into the hind paw induced mechanical allodynia in both the injected and intact hind paws, and the ketogenic diet alleviated mechanical allodynia in both hind paws. In addition, the ketogenic diet prevented formalin-induced edema. Furthermore, the diet alleviated mechanical allodynia induced by peripheral nerve injury. Thus, these findings indicate that a ketogenic diet has a therapeutic effect on chronic pain induced by inflammation and nerve injury.
Asunto(s)
Dolor Crónico , Dieta Cetogénica , Neuralgia , Ratones , Masculino , Animales , Hiperalgesia/tratamiento farmacológico , Inflamación/metabolismo , Formaldehído/efectos adversos , Modelos Animales de EnfermedadRESUMEN
The heart receives sympathetic and parasympathetic innervation through the intrinsic cardiac nervous system. Although bradykinin (BK) has negative inotropic and chronotropic properties of cardiac contraction, the direct effect of BK on the intrinsic neural network of the heart is still unclear. In the present study, the effect of BK on the intracardiac ganglion neurons isolated from rats was investigated using the perforated patch-clamp technique. Under current-clamp conditions, application of 0.1⯵M BK depolarized the membrane, accompanied by repetitive firing of action potentials. When BK was applied repeatedly, the second responses were considerably less intense than the first application. The BK action was fully inhibited by the B2 receptor antagonist Hoe-140, but not by the B1 receptor antagonist des-Arg9-[Leu8]-BK. The BK response was mimicked by the B2 agonist [Hyp3]-BK. The BK-induced depolarization was inhibited by the phospholipase C inhibitor U-73122. BK evoked inward currents under voltage-clamp conditions at a holding potential of -60â¯mV. Removal of extracellular Ca2+ markedly increased the BK-induced currents, suggesting an involvement of Ca2+-permeable non-selective cation channels. The muscarinic agonist oxotremorine-M (OxoM) also elicited the extracellular Ca2+-sensitive cationic currents. The OxoM response did not exhibit rundown with repeated agonist application. The amplitude of current evoked by 1⯵M OxoM was comparable to that induced by 0.1⯵M BK. Co-application of 0.1⯵M BK and 1⯵M OxoM elicited the current whose peak amplitude was almost the same as that elicited by OxoM alone, suggesting that BK and OxoM activate same cation channels. BK also reduced the amplitude of M-current, while the M-current inhibitor XE-991 affected neither resting membrane potential nor the BK-induced depolarization. From these results, we suggest that BK regulates excitability of intrinsic cardiac neurons by both an activation of non-selective cation channels and an inhibition of M-type K+ channels through B2 receptors.
Asunto(s)
Potenciales de Acción/efectos de los fármacos , Bradiquinina/farmacología , Sistema de Conducción Cardíaco/efectos de los fármacos , Corazón/inervación , Neuronas/efectos de los fármacos , Animales , Técnicas de Placa-Clamp , Ratas , Ratas WistarRESUMEN
The dopaminergic neural system plays a crucial role in motor regulation as well as regulation of anxiety-related behaviors. Although rats with neonatal dopamine depletion exhibit motor hyperactivity and have been utilized as animal models of attention deficit hyperactivity disorder, characterization of their behavior under anxiogenic conditions is lacking. In the present study, we investigated behavioral responses to anxiogenic stimuli in young adult rats with neonatal dopamine depletion using the open field (OF), elevated plus maze (EPM), and light/dark (L/B) box tests. The OF and EPM tests were performed under low-light and bright-light conditions. The ameliorative effects of pretreatment with methamphetamine (MAP) or atomoxetine (ATX) on abnormal behaviors induced by neonatal dopamine depletion were also assessed. Rats that underwent 6-hydroxydopamine treatment 4â¯day after birth showed significant increases in motor activity and decreases in anxiety-related behaviors in OF tests under both conditions and in EPM tests under bright-light conditions. Furthermore, rats with neonatal dopamine depletion did not show normal behavioral responsiveness to changes in the intensity of anxiogenic stimuli. Pretreatment with MAP (4â¯mg/kg) and ATX (1.2â¯mg/kg/day) ameliorated motor hyperactivity but not abnormal anxiety-related behaviors. These results suggest that the dopaminergic system plays a crucial role in the development of neural networks involved in locomotion as well as in those involved in anxiety-related behavior. The results indicate that the mechanisms underlying the abnormal anxiolytic responses partially differ from those underlying motor hyperactivity.
Asunto(s)
Ansiedad/psicología , Conducta Animal , Dopamina/deficiencia , Inhibidores de Captación Adrenérgica/farmacología , Animales , Animales Recién Nacidos , Clorhidrato de Atomoxetina/farmacología , Dopamina/fisiología , Inhibidores de Captación de Dopamina/farmacología , Conducta Exploratoria , Femenino , Iluminación , Aprendizaje por Laberinto , Metanfetamina/farmacología , Actividad Motora , Red Nerviosa/crecimiento & desarrollo , Red Nerviosa/fisiología , Oxidopamina , Embarazo , Ratas , Ratas WistarRESUMEN
Rovatirelin ([1-[-[(4S,5S)-(5-methyl-2-oxo oxazolidin-4-yl) carbonyl]-3-(thiazol-4-yl)-l-alanyl]-(2R)-2-methylpyrrolidine) is a novel synthetic agent that mimics the actions of thyrotropin-releasing hormone (TRH). The aim of this study was to investigate the electrophysiological and pharmacological effects of rovatirelin on the central noradrenergic system and to compare the results with those of another TRH mimetic agent, taltirelin, which is approved for the treatment of spinocerebellar degeneration (SCD) in Japan. Rovatirelin binds to the human TRH receptor with higher affinity (Ki=702nM) than taltirelin (Ki=3877nM). Rovatirelin increased the spontaneous firing of action potentials in the acutely isolated noradrenergic neurons of rat locus coeruleus (LC). The facilitatory action of rovatirelin on the firing rate in the LC neurons was inhibited by the TRH receptor antagonist, chlordiazepoxide. Reduction of the extracellular pH increased the spontaneous firing of LC neurons and rovatirelin failed to increase the firing frequency further, indicating an involvement of acid-sensitive K+ channels in the rovatirelin action. In in vivo studies, oral administration of rovatirelin increased both c-Fos expression in the LC and extracellular levels of noradrenaline (NA) in the medial prefrontal cortex (mPFC) of rats. Furthermore, rovatirelin increased locomotor activity. The increase in NA level and locomotor activity by rovatirelin was more potent and longer acting than those by taltirelin. These results indicate that rovatirelin exerts a central nervous system (CNS)-mediated action through the central noradrenergic system, which is more potent than taltirelin. Thus, rovatirelin may have an orally effective therapeutic potential in patients with SCD.
Asunto(s)
Neuronas Adrenérgicas/efectos de los fármacos , Locus Coeruleus/efectos de los fármacos , Oxazolidinonas/farmacología , Corteza Prefrontal/efectos de los fármacos , Pirrolidinas/farmacología , Hormona Liberadora de Tirotropina/farmacología , Potenciales de Acción , Administración Oral , Neuronas Adrenérgicas/metabolismo , Animales , Relación Dosis-Respuesta a Droga , Ligandos , Locus Coeruleus/citología , Locus Coeruleus/metabolismo , Masculino , Microdiálisis , Actividad Motora/efectos de los fármacos , Norepinefrina/metabolismo , Oxazolidinonas/administración & dosificación , Oxazolidinonas/metabolismo , Corteza Prefrontal/citología , Corteza Prefrontal/metabolismo , Unión Proteica , Proteínas Proto-Oncogénicas c-fos/metabolismo , Pirrolidinas/administración & dosificación , Pirrolidinas/metabolismo , Ensayo de Unión Radioligante , Ratas Sprague-Dawley , Ratas Wistar , Receptores de Hormona Liberadora de Tirotropina/agonistas , Receptores de Hormona Liberadora de Tirotropina/metabolismo , Hormona Liberadora de Tirotropina/administración & dosificación , Hormona Liberadora de Tirotropina/análogos & derivados , Hormona Liberadora de Tirotropina/metabolismo , Factores de TiempoRESUMEN
Modulation of the membrane excitability of rat parasympathetic intracardiac ganglion neurons by muscarinic receptors was studied using an amphotericin B-perforated patch-clamp recording configuration. Activation of muscarinic receptors by oxotremorine-M (OxoM) depolarized the membrane, accompanied by repetitive action potentials. OxoM evoked inward currents under voltage-clamp conditions at a holding potential of -60 mV. Removal of extracellular Ca(2+) markedly increased the OxoM-induced current (IOxoM). The inward IOxoM in the absence of extracellular Ca(2+) was fully inhibited by removal of extracellular Na(+), indicating the involvement of non-selective cation channels. The IOxoM was inhibited by organic cation channel antagonists including SKF-96365 and ML-204. The IOxoM was antagonized by muscarinic receptor antagonists with the following potency: 4-DAMP > pirenzepine = darifenacin > methoctramine. Muscarinic toxin 7 (MT-7), a highly selective inhibitor for M1 receptor, produced partial inhibition of the IOxoM. In the presence of MT-7, concentration-inhibition curve of the M3-preferring antagonist darifenacin was shifted to the left. These results suggest the contribution of M1 and M3 receptors to the OxoM response. The IOxoM was inhibited by U-73122, a phospholipase C inhibitor. The membrane-permeable IP3 receptor blocker xestospongin C also inhibited the IOxoM. Furthermore, pretreatment with thapsigargin and BAPTA-AM inhibited the IOxoM, while KN-62, a blocker of Ca(2+)/calmodulin-dependent protein kinase II, had no effect. These results suggest that the activation mechanism involves a PLC pathway, release of Ca(2+) from intracellular Ca(2+) stores and calmodulin. The cation channels activated by muscarinic receptors may play an important role in neuronal membrane depolarization in rat intracardiac ganglion neurons.
Asunto(s)
Ganglios Parasimpáticos/fisiología , Neuronas/fisiología , Receptor Muscarínico M1/metabolismo , Receptor Muscarínico M3/metabolismo , Animales , Calcio/metabolismo , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/antagonistas & inhibidores , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/metabolismo , Calmodulina/metabolismo , Células Cultivadas , Ganglios Parasimpáticos/efectos de los fármacos , Potenciales de la Membrana/efectos de los fármacos , Potenciales de la Membrana/fisiología , Agonistas Muscarínicos/farmacología , Neuronas/efectos de los fármacos , Oxotremorina/análogos & derivados , Oxotremorina/farmacología , Técnicas de Placa-Clamp , Ratas Wistar , Receptor Muscarínico M1/agonistas , Receptor Muscarínico M3/agonistas , Sodio/metabolismo , Fosfolipasas de Tipo C/antagonistas & inhibidores , Fosfolipasas de Tipo C/metabolismoRESUMEN
The use of NR2B antagonists in Parkinsonism is still controversial. To examine their anti-parkinsonian effects, the NR2B antagonist, ifenprodil, and L-DOPA were administered together and separately in hemiparkinsonian rats (hemi-PD) that were subjected to a cylinder test. Recovery from hypoactivity was achieved by single administration of 3-7 mg/kg of L-DOPA; however, improvement in the deficit of bilateral forelimb use was not observed. When administered alone, ifenprodil had no anti-parkinsonian effects; however, combined administration of ifenprodil and 7 mg/kg of L-DOPA significantly reversed the deficit of bilateral forelimb use without adversely affecting the L-DOPA-induced improvement in motor activity. Next, in order to identify the brain area influenced by L-DOPA and ifenprodil, quantitative analysis of L-DOPA-induced c-Fos immunoreactivity was performed in various brain areas of hemi-PD following administration of L-dopa with and without ifenprodil. Among brain areas with robust c-Fos expression within the motor loop circuit in dopamine-depleted hemispheres, co-administered ifenprodil markedly attenuated L-DOPA-induced c-Fos expression in only the subthalamic nucleus (STN), suggesting that the STN is the primary target for the anti-parkinsonian action of NR2B antagonists.
Asunto(s)
Antiparkinsonianos/administración & dosificación , Levodopa/administración & dosificación , Trastornos Parkinsonianos/prevención & control , Piperidinas/administración & dosificación , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Miembro Anterior , Masculino , Actividad Motora/efectos de los fármacos , Trastornos Parkinsonianos/inducido químicamente , Proteínas Proto-Oncogénicas c-fos/metabolismo , Ratas , Ratas Wistar , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Núcleo Subtalámico/efectos de los fármacos , Núcleo Subtalámico/metabolismoRESUMEN
Paclitaxel, one of the chemotherapeutic agents clinically used to treat several types of cancer, produces side effects such as peripheral neuropathy, sensory abnormalities, and hyperalgesia. Since hyperalgesia remains after cessation of paclitaxel therapy and becomes chronic, we hypothesize that alteration in memory and the cognitive process of pain underlies hyperalgesia. To test this hypothesis, we examined whether drug-induced hyperalgesia alters the affective component of pain and the NMDA-NR1 and mGluR1 receptors as a mediator for signal transmission and memory of pain. Mechanical sensitivity was measured by von Frey filament test after intraperitoneal injection of paclitaxel in rats. Paclitaxel-induced hyperalgesia was confirmed over almost the entire 14-day period of observation after the treatment. The effect of paclitaxel-induced hyperalgesia on the affective component of pain was assessed using pain-induced place aversion. The formalin-induced conditioned place aversion was completely abolished in the paclitaxel-treated rats. Immunoblot analysis of NR1 and mGluR1 protein levels in various brain regions was performed after paclitaxel treatment. Treatment reduced only the NR1 expression within the frontal cortex. These results suggest that the hypofunction of memory processes with the reduced NMDA receptors in the frontal cortex might be involved in the expression of abnormal emotional behaviors accompanied by hyperalgesia.
Asunto(s)
Antineoplásicos Fitogénicos/toxicidad , Lóbulo Frontal/efectos de los fármacos , Hiperalgesia/inducido químicamente , Hiperalgesia/patología , Paclitaxel/toxicidad , Receptores de N-Metil-D-Aspartato/metabolismo , Análisis de Varianza , Animales , Condicionamiento Operante/efectos de los fármacos , Formaldehído/efectos adversos , Lóbulo Frontal/metabolismo , Calor/efectos adversos , Masculino , Nocicepción/efectos de los fármacos , Nocicepción/fisiología , Dimensión del Dolor , Umbral del Dolor/efectos de los fármacos , Ratas , Ratas Wistar , Receptores de N-Metil-D-Aspartato/genéticaRESUMEN
BACKGROUND: Neutrophils play an essential role in innate immunity and against infection. Mitochondria are organelles that produce energy in the form of adenosine triphosphate (ATP), which is required for maintaining the function and structure of cells and organs. Although local anesthetics (LAs) are widely used in clinical practice, it remains unclear whether LAs such as lidocaine, ropivacaine, and bupivacaine affect neutrophil mitochondrial functions. The aim of this study was to examine whether LAs have any effects on human neutrophil mitochondrial functions. METHODS: Freshly isolated human neutrophils were incubated with lidocaine, ropivacaine, or bupivacaine. The oxidative burst and phagocytic activity of neutrophils and apoptotic rate of neutrophils were measured to assess the effect of LAs on neutrophil functions. The ATP concentration, mitochondrial transmembrane potential (Deltapsim), and neutrophil mitochondrial morphology were also measured to evaluate the effect of LAs on mitochondrial functions. RESULTS: Lidocaine (400 microm) induced a reduction in the oxidative burst and phagocytosis activity of neutrophils by approximately 20%. The ATP concentration was significantly lower in lidocain-treated neutrophils compared with control neutrophils (876 +/- 25 vs. 1,332 +/- 76 pmol/10(6) neutrophils; p < 0.05). Mitochondrial transmembrane potential (Deltapsim) was also significantly lower in lidocaine-treated neutrophils compared with control neutrophils (p < 0.05). Lidocaine also induced mitochondrial structural changes and induced apoptosis of neutrophils. Ropivacaine and bupivacaine had no effect on neutrophil functions including mitochondrial function. Furthermore, the study of mitochondrial function depletion demonstrated that neutrophil function requires active mitochondrial function. CONCLUSIONS: Although ropivacaine and bupivacaine had no effect on neutrophil and mitochondrial functions, lidocaine suppressed neutrophil function, inhibited ATP synthesis, reduced mitochondrial membrane potential, and induced apoptosis.
Asunto(s)
Anestésicos Locales/farmacología , Lidocaína/farmacología , Mitocondrias/efectos de los fármacos , Neutrófilos/fisiología , Amidas/farmacología , Apoptosis/efectos de los fármacos , Apoptosis/fisiología , Bupivacaína/farmacología , Células Cultivadas , Humanos , Mitocondrias/fisiología , Neutrófilos/efectos de los fármacos , Fagocitosis/efectos de los fármacos , RopivacaínaRESUMEN
To test the hypothesis that the cellular mechanism whereby chronic deep brain stimulation of the subthalamic nucleus (STN-DBS) induces the improvement of motor deficits lasting after stimulation in the hemiparkinsonian (hemi-PD) rat involves the NMDA receptor-dependent processes in neurons receiving afferents from the STN, we examined whether the NMDA receptor antagonist prevents the alleviating after-effect of repeated STN-DBS on motor deficits in hemi-PD. The cylinder test was performed before and after repeated STN-DBS over 3 days in hemi-PD that received a unilateral injection of 6-OHDA into the medial forebrain bundle 3 weeks prior to STN-DBS experiments. No significant improvement in the reduced frequency of forelimb use and forelimb-use asymmetry was seen in the cylinder test after the single STN-DBS, while, when the STN-DBS was applied three times at intervals of 24 h, the improvement became apparent and significant only in the reduced frequency of forelimb use (akinesia) after termination of the stimulation, suggesting the alleviating after-effect of chronic stimulation. Then, the effects of intraperitoneal administration of the non-competitive NMDA receptor antagonist MK-801 and the competitive NMDA receptor antagonist CPP on the alleviating after-effect of the STN-DBS were examined in cylinder tests performed before and after repeated STN-DBS for 3 days in hemi-PD. Both MK-801 (0.1 mg/kg) and CPP (0.5 mg/kg) completely prevented the improvement of the akinetic motor deficit after repeated STN-DBS. These results support the hypothesis that activation of the NMDA receptor and subsequent cellular processes in neurons receiving the afferents from the STN may involve in the mechanism underlying the alleviating after-effect of chronic STN-DBS on the akinetic motor deficit in hemi-PD.
Asunto(s)
Estimulación Encefálica Profunda , Discinesias/terapia , Trastornos Parkinsonianos/terapia , Receptores de N-Metil-D-Aspartato/metabolismo , Núcleo Subtalámico/fisiopatología , Animales , Maleato de Dizocilpina/farmacología , Discinesias/fisiopatología , Antagonistas de Aminoácidos Excitadores/farmacología , Miembro Anterior , Masculino , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiología , Pruebas Neuropsicológicas , Oxidopamina , Trastornos Parkinsonianos/inducido químicamente , Trastornos Parkinsonianos/fisiopatología , Piperazinas/farmacología , Ratas , Ratas Wistar , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Núcleo Subtalámico/efectos de los fármacos , Factores de TiempoRESUMEN
BACKGROUND: Acute alcohol intoxication is associated with increased susceptibility to infection. In host defense, the expression of adhesion molecules such as beta2-integrin and l-selectin on leukocytes is involved in leukocyte migration to inflamed organ tissue. To elucidate the mechanisms underlying the immunosuppressive effects of ethanol, we investigated whether ethanol pretreatment may influence the changes in adhesion molecule expression induced by lipopolysaccharide (LPS) or interleukin (IL)-8 in human whole blood. METHODS: Ethanol was added to samples of human whole blood (final concentration: 0%, 0.2%, 0.4%, and 0.8%). Samples were assigned to an unstimulated group and an LPS-stimulated group. In another set of experiments, stimulation was induced by IL-8. After fluorescence labeling of alphaM-subunit of beta2-integrin (CD11b) and l-selectin (CD62L), the expression of CD11b and CD62L were measured using flow cytometry. RESULTS: Stimulation with LPS significantly upregulated CD11b expression (5.9 +/- 0.9 to 16.3 +/- 1.8, p < 0.05). Ethanol inhibited this LPS-induced upregulation of CD11b (p < 0.001). Stimulation with IL-8 significantly upregulated CD11b expression (5.3 +/- 1.7 to 7.5 +/- 2.7, p < 0.01) and this IL-8-induced upregulation of CD11b was also inhibited by ethanol pretreatment (p < 0.001). In contrast, ethanol did not modify CD62L expression in either unstimulated or stimulated groups. CONCLUSION: The impairment of CD11b expression on leukocytes suggests that alcohol intake interferes with the migration of leukocytes to sites of inflammation, which may explain, in part, why alcohol intoxication increases susceptibility to infection.
Asunto(s)
Antiinfecciosos Locales/farmacología , Antígenos CD18/efectos de los fármacos , Etanol/farmacología , Selectina L/efectos de los fármacos , Leucocitos/metabolismo , Antígenos CD18/sangre , Supervivencia Celular , Humanos , Técnicas In Vitro , Interleucina-8 , Selectina L/sangre , Lipopolisacáridos , Masculino , Valores de ReferenciaRESUMEN
To produce an animal model of a dopa-responsive motor disorder with depletion of dopamine (DA) release in the striatum by dysfunction of the transmitter release machinery of the nigrostriatal DA system, we performed an intra-nigral injection of an HVJ-liposome gene transfer vector containing antisense oligodeoxynucleotides (ODNs) against synaptotagmin I (SytI), a key regulator of Ca(2+)-dependent exocytosis and endocytosis in adult rats. A unilateral intra-nigral injection of HVJ-liposome vectors containing antisense ODNs against SytI (syt-AS) caused a moderate disruption of methamphetamine-induced release of DA in the treated side of the striatum, while the syt-AS treatment did not affect physiological release of DA in the treated striatum. A bilateral intra-nigral injection of HVJ-liposome vectors containing syt-AS induced an impairment of the striatal DA-mediated acquisition of skilled behavior in a rotarod task without any deficits in general motor functions, such as spontaneous locomotor activity, motor adjusting steps, equilibrium function, or muscle strength. These findings suggest that an intra-nigral treatment with HVJ-liposome vectors containing syt-AS may cause a long-lasting nigral knockdown of SytI which, in turn, leads to a moderate dysfunction of the DA release machinery in the terminals of the nigrostriatal DA system and a subsequent mild depletion of DA release in the striatum.
Asunto(s)
Cuerpo Estriado/metabolismo , Técnicas de Transferencia de Gen , Actividad Motora/fisiología , Trastornos de la Destreza Motora/fisiopatología , Oligonucleótidos Antisentido/administración & dosificación , Sustancia Negra/efectos de los fármacos , Análisis de Varianza , Animales , Conducta Animal , Cuerpo Estriado/virología , Modelos Animales de Enfermedad , Dopamina/metabolismo , Inmunohistoquímica/métodos , Masculino , Metanfetamina/toxicidad , Microdiálisis/métodos , Actividad Motora/efectos de los fármacos , Destreza Motora/efectos de los fármacos , Destreza Motora/fisiología , Trastornos de la Destreza Motora/etiología , Trastornos de la Destreza Motora/metabolismo , Oligonucleótidos Antisentido/genética , Oxidopamina/toxicidad , Ratas , Ratas Wistar , Tiempo de Reacción/efectos de los fármacos , Tiempo de Reacción/fisiología , Prueba de Desempeño de Rotación con Aceleración Constante/métodos , Sustancia Negra/lesiones , Sustancia Negra/virología , Sinaptotagmina I/deficienciaRESUMEN
Gerstmann-Sträussler-Scheinker Syndrome (GSS) is a rare, infectious syndrome related to a mutation in the prion protein. A 60-yr-old, 152-cm, 31-kg woman with GSS was scheduled for open gastrostomy. This is the first report about an anesthetic experience in a patient with GSS. We describe our experience and precautions in the anesthetic management of a GSS patient.
Asunto(s)
Anestesia/métodos , Enfermedad de Gerstmann-Straussler-Scheinker/cirugía , Mutación/genética , Priones/genética , Obstrucción de las Vías Aéreas/prevención & control , Contaminación de Equipos/prevención & control , Femenino , Enfermedad de Gerstmann-Straussler-Scheinker/genética , Humanos , Intubación Intratraqueal/instrumentación , Intubación Intratraqueal/métodos , Persona de Mediana EdadRESUMEN
Leukocyte adhesion to endothelial cells plays a pivotal role in the early stage of endotoxin shock. The attenuation of the leukocyte response to endotoxin may contribute to the prevention of further organ dysfunction. Recent evidence implies that N-acetyl-cysteine (NAC) attenuates endotoxin-induced pathophysiological changes. We investigated the effect of NAC on the expression of CD11b and CD62L in endotoxin-stimulated human whole blood. NAC (>10 mM) significantly inhibited the lipopolysaccharide (LPS)-induced upregulation of CD11b in a concentration-dependent manner. However, NAC did not affect the LPS-induced downregulation of CD62L. We also analyzed the effect of NAC on interleukin-8 (IL-8)-induced expression of CD11b in human whole blood. IL-8 (10 ng/mL) significantly upregulated the expression of CD11b, and the IL-8-induced upregulation was significantly attenuated by NAC (>10 mM) in a dose-dependent manner. We conclude that NAC attenuates the increased expression of CD11b in either LPS or IL-8-stimulated human whole blood.
Asunto(s)
Acetilcisteína/farmacología , Antígeno CD11b/biosíntesis , Moléculas de Adhesión Celular/biosíntesis , Endotoxinas/farmacología , Relación Dosis-Respuesta a Droga , Humanos , Interleucina-8/farmacología , Selectina L/biosíntesis , Leucocitos/metabolismoRESUMEN
PURPOSE: Catastrophic antiphospholipid syndrome (CAPS) is a variant of antiphospholipid syndrome and presents with life-threatening symptoms of multiorgan failure due to thrombosis. We present a patient with CAPS secondary to an ovarian cancer. In such cases, it is believed that the thrombotic risk disappears after surgical removal of the cancer. The intraoperative management was challenging because of the risks of two opposing complications: catastrophic exacerbation of the thrombotic tendency triggered by the surgical stimulus and major bleeding due to the necessary anticoagulation. We describe the intraoperative management of hemostasis in a patient with CAPS. CLINICAL FEATURES: A 44-yr-old female patient with CAPS underwent resection of an ovarian cancer, which was suspected to be associated with her coagulation abnormality. She had both arterial and venous thromboembolism, including cerebral infarction, embolic gangrene, and pulmonary emboli. Serological examinations revealed increased anticardiolipin IgG antibody and decreased protein C activity. Before surgery, an inferior vena cava filter was placed to prevent perioperative pulmonary embolism. Prostaglandin E(1) (PGE(1); 100 ng.kg(-1).min(-1)) was given intraoperatively to suppress platelet aggregation and thrombin generation and to maintain arterial blood flow. No apparent coagulation abnormalities were observed during surgery, neither hypercoagulation nor a tendency to bleed. No additional thrombotic symptoms developed during a six-month follow-up. CONCLUSION: The use of PGE(1), an inhibitor of thrombin formation and platelet function, and placement of an inferior vena cava filter were associated with the uneventful surgical resection of an ovarian cancer in a patient with CAPS.
Asunto(s)
Alprostadil/uso terapéutico , Síndrome Antifosfolípido/complicaciones , Trombosis/prevención & control , Adulto , Anticoagulantes/uso terapéutico , Síndrome Antifosfolípido/etiología , Femenino , Hemostasis , Humanos , Cuidados Intraoperatorios , Neoplasias Ováricas/complicaciones , Neoplasias Ováricas/cirugía , Circulación PulmonarRESUMEN
In view of recent findings that suggest that the nigrostriatal dopamine (DA) system plays a role in motor control and the acquisition of habits and skills, we hypothesized that the striatum-based function underlying the acquisition of skilled behaviors might be more vulnerable to dopamine depletion than the motor control. To test this hypothesis, we investigated whether impaired acquisition of skilled behaviors occurs in a pre-symptomatic stage model of Parkinson's disease (PD). By using the microdialysis method and the 6-OHDA-technique to destroy dopamine neurons, we confirmed that rats with unilateral partial lesions of the nigral dopamine cells by 6-OHDA are suitable for a pre-symptomatic stage model of Parkinson's disease. The rats in this model exhibited moderate disruption of striatal dopamine release function and relatively intact motor functions. In a rotarod test, the impaired acquisition of skilled behavior occurred in rats with bilateral partial lesions of the nigral dopamine cells by 6-OHDA. These rats displayed intact general motor functions, such as locomotor activity, adjusting steps, equilibrium function and muscle strength. Based on these results, we concluded that the striatum-based function underlying the acquisition of skilled behaviors or sensorimotor learning may be more vulnerable to dopamine depletion than the motor control.
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Cuerpo Estriado/metabolismo , Dopamina/deficiencia , Destreza Motora/fisiología , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/fisiopatología , Anfetamina/farmacología , Animales , Conducta Animal , Recuento de Células/métodos , Supervivencia Celular/efectos de los fármacos , Estimulantes del Sistema Nervioso Central/farmacología , Cuerpo Estriado/efectos de los fármacos , Modelos Animales de Enfermedad , Conducta Exploratoria/efectos de los fármacos , Lateralidad Funcional , Suspensión Trasera/métodos , Inmunohistoquímica/métodos , Masculino , Haz Prosencefálico Medial/efectos de los fármacos , Haz Prosencefálico Medial/metabolismo , Microdiálisis/métodos , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiología , Oxidopamina/toxicidad , Enfermedad de Parkinson/etiología , Ratas , Ratas Wistar , Análisis de Regresión , Prueba de Desempeño de Rotación con Aceleración Constante/métodos , Sustancia Negra/efectos de los fármacos , Sustancia Negra/metabolismo , Simpaticolíticos/toxicidad , Factores de Tiempo , Tirosina 3-Monooxigenasa/metabolismoRESUMEN
UNLABELLED: We previously reported that a platelet-activating factor receptor (PAFR) antagonist (TCV-309) suppressed lipopolysaccharide (LPS)-induced mortality and tumor necrosis factor (TNF) production in mice. However, the effect of TCV-309 on cytokine production induced by Staphylococcus enterotoxin B (SEB) or live bacteria has not been reported. In this study we investigated the effect of TCV-309 on cytokine production in human whole blood induced by LPS, SEB, and both Gram-positive and -negative bacteria. Human whole blood diluted 5:1 (980 microL) was placed in the wells of a 24-well plate. Ten microliters of LPS, SEB, Escherichia coli O18 K(+), or Staphylococcus aureus were added to each well. After incubation at 37 degrees C for 6 h, TNF, interleukin (IL)-6, and IL-8 in the culture medium were measured. TCV-309 did not affect the growth of either E. coli or S. aureus bacteria in the culture medium for the 6 h incubation. LPS, SEB, and both E. coli and S. aureus induced TNF, IL-6, and IL-8 in human whole blood. TCV-309 significantly inhibited the production of TNF, IL-6, and IL-8 induced by LPS, SEB, and bacteria. A PAFR antagonist suppressed cytokine production induced by LPS, SEB, and both Gram-positive and -negative bacteria in human whole blood. A PAFR plays an important role of producing proinflammatory cytokines induced by both toxins and live bacteria. IMPLICATIONS: The platelet-activating factor receptor plays an important role in producing proinflammatory cytokines induced by bacterial toxins, such as lipopolysaccharide,Staphylococcus enterotoxin B, and live Gram-positive and Gram-negative bacteria.
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Toxinas Bacterianas/farmacología , Citocinas/antagonistas & inhibidores , Citocinas/sangre , Glicoproteínas de Membrana Plaquetaria/antagonistas & inhibidores , Receptores Acoplados a Proteínas G/antagonistas & inhibidores , Antígenos Bacterianos/metabolismo , Citocinas/biosíntesis , Enterotoxinas/metabolismo , Escherichia coli/metabolismo , Humanos , Masculino , Glicoproteínas de Membrana Plaquetaria/metabolismo , Compuestos de Piridinio/farmacología , Receptores Acoplados a Proteínas G/metabolismo , Staphylococcus aureus/metabolismo , Tetrahidroisoquinolinas/farmacologíaRESUMEN
UNLABELLED: It has been demonstrated that local anesthetics have several effects on the immune system. Monocytes and macrophages are essential components of the host response to microbial infection; however, the effect of local anesthetics on monocyte surface receptor expression remains unclear. We designed this study to investigate the effects of local anesthetics on monocyte mCD14 and human leukocyte antigen (HLA)-DR expression and lipopolysaccharide (LPS)-induced or staphylococcal enterotoxin B (SEB)-induced tumor necrosis factor (TNF)-alpha production. Blood samples were obtained from 10 healthy volunteers. The effects of local anesthetics on LPS- or SEB-induced TNF-alpha production were determined by using an enzyme-linked immunosorbent assay. After different doses of local anesthetics were added, the blood was stimulated with LPS (10 ng/mL) or SEB (10 micro g/mL) for 4 h. The effects of local anesthetics on monocyte mCD14 and HLA-DR expression were measured by dual monoclonal antibody staining and flow cytometry. Local anesthetics showed no effect on LPS- or SEB-induced TNF-alpha production in human whole blood. Local anesthetics suppressed monocyte HLA-DR expression in a dose-dependent manner (P < 0.05) but had no effect on monocyte mCD14 expression. This study demonstrated that local anesthetics suppress HLA-DR expression on the surface of human monocytes. IMPLICATIONS: Monocyte surface receptors have a crucial role in the host response to microbial infection. We investigated the effects of local anesthetics on monocyte mCD14 and human leukocyte antigen (HLA)-DR expression. Our results show that local anesthetics suppress HLA-DR expression on the surface of human monocytes.
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Anestésicos Locales/farmacología , Antígenos HLA-DR/biosíntesis , Receptores de Lipopolisacáridos/biosíntesis , Monocitos/metabolismo , Adulto , Bupivacaína/farmacología , Relación Dosis-Respuesta a Droga , Enterotoxinas/farmacología , Ensayo de Inmunoadsorción Enzimática , Humanos , Técnicas In Vitro , Lidocaína/farmacología , Lipopolisacáridos/farmacología , Masculino , Mepivacaína/farmacología , Monocitos/efectos de los fármacos , Factor de Necrosis Tumoral alfa/biosíntesisRESUMEN
UNLABELLED: We studied the effects of pneumoperitoneum on gastric submucosal perfusion metabolism during elective laparoscopic cholecystectomy (LASC) by measuring the PCO(2) gap, defined as the difference between intramucosal PCO(2) and arterial PCO(2), using gas tonometry in 20 patients. Furthermore, we examined whether thoracic epidural anesthesia (TEA) affects gastric submucosal perfusion metabolism during LASC. Patients were randomly allocated to receive general anesthesia (group G, n = 10) or general anesthesia combined with TEA (group E, n = 10). In both groups, the PCO(2) gap increased significantly during pneumoperitoneum and remained at this level until the end of surgery compared with the baseline value. There were no significant differences in PCO(2) gap values between the two groups at any time sampled. These results suggested that pneumoperitoneum significantly impaired gastric submucosal perfusion and metabolism and that TEA did not attenuate the impairment of gastric submucosal perfusion during or after pneumoperitoneum. IMPLICATIONS: We investigated the effect of pneumoperitoneum on gastric submucosal perfusion by measuring PCO(2) gap with the use of gas tonometry. PCO(2) gap significantly increased during and after the pneumoperitoneum compared with the control level. Thoracic epidural anesthesia did not attenuate this inhibition.
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Anestesia Epidural , Dióxido de Carbono/sangre , Colecistectomía Laparoscópica/efectos adversos , Adulto , Anciano , Bicarbonatos/sangre , Análisis de los Gases de la Sangre , Presión Sanguínea/fisiología , Femenino , Mucosa Gástrica/irrigación sanguínea , Humanos , Concentración de Iones de Hidrógeno , Masculino , Persona de Mediana Edad , Neumoperitoneo Artificial , Flujo Sanguíneo Regional/efectos de los fármacos , Flujo Sanguíneo Regional/fisiologíaRESUMEN
To examine the role of mGluR1 (a subunit of the group I metabotropic glutamate receptor) in the nociceptive responses of rats following a subcutaneous injection of formalin into the plantar surface of the hind paw, we delivered antisense oligonucleotides (ODNs) against mGluR1 into the rat lumbar spinal cord (L3-L5) intrathecally using an HVJ-liposome-mediated gene transfer method. Rats treated with a single injection of mGluR1 antisense ODNs into the intrathecal space of the lumbar spinal cord showed a marked reduction of the early-sustained phase of formalin-induced nociceptive responses, but not of their acute phase. The reduction of nociceptive behavioral responses became apparent at day 2 after the antisense treatment and lasted for 2 days. This corresponded to a long-lasting down-regulation (46%) of mGluR1 expression in the lumbar cord. This down-regulated mGluR1 was observed at day 2 and persisted until day 4 after the intrathecal infusion of mGluR1 antisense ODN. In contrast, rats treated with mGluR1 sense or mismatch ODNs showed none of these changes. These results suggest that mGluR1 may play a crucial role in the sustained nociception of formalin-induced behavioral responses.
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Oligonucleótidos Antisentido/administración & dosificación , Dimensión del Dolor/efectos de los fármacos , Receptores de Glutamato Metabotrópico/biosíntesis , Receptores de Glutamato Metabotrópico/deficiencia , Médula Espinal/metabolismo , Animales , Regulación hacia Abajo/efectos de los fármacos , Regulación hacia Abajo/fisiología , Técnicas de Transferencia de Gen , Masculino , Oligonucleótidos Antisentido/genética , Dimensión del Dolor/métodos , Ratas , Ratas Wistar , Receptores de Glutamato Metabotrópico/genética , Médula Espinal/efectos de los fármacosRESUMEN
The vapor of formaldehyde has been reported to represent a potential health hazard, resulting in respiratory dysfunction. To determine the potential role of alterations in the alveolar macrophages induced by inhalation of formaldehyde, we studied the cytokine production of murine alveolar macrophages. Mice were exposed at 0, 2.5, 5, 10 ppm of formaldehyde for 16 hrs daily, respectively. Durations of inhalation were 7, 14, 21 and 28 days. Immediately after the formaldehyde exposure, murine alveolar macrophages were harvested from the mice. 18 hrs after LPS stimulation, the cytokines (IL-4, IL-10, IFN-gamma, TNF-alpha) were measured in the supernatant of cultured murine alveolar macrophages using the ELISA method. No levels of formaldehyde exposure changed these cytokine productions. Either our dose or duration of formaldehyde exposure might not have been enough to produce significant changes of cytokine production of murine alveolar macrophages. Further experiments with low but longer formaldehyde exposure may be needed to understand the effect of formaldehyde on cytokine production.