RESUMEN
Pyrrosia lingua (Thunb.) Farw is a common plant that has been widely used as a traditional herbal medicine in China and Korea to treat patients suffering from pain, vaginal bleeding and urolithiasis. However, the pharmacological effects of P. lingua on bone remain unknown. We investigated the anti-osteoporotic effects of an ethanolic extract of P. lingua (EEPL). We found that EEPL suppressed osteoclast differentiation by directly acting on osteoclast precursor cells. EEPL suppressed the expression of receptor activator of nuclear factor-κB ligand (RANKL)-induced nuclear factor of activated T cells 1, a major transcription factor for osteoclastogenesis, by inhibiting RANKL-induced expression of aryl hydrocarbon receptor/c-Fos, and activation of nuclear factor-κB and mitogen-activated protein kinases. Moreover, administration of EEPL inhibited trabecular bone loss and weight gain in ovariectomized mice. Furthermore, we identified phytochemicals in EEPL that are known to exert anti-osteoclastogenic or anti-osteoporotic effects using ultra-high-performance liquid chromatography-tandem mass-spectrometry analysis. Overall, the results of this study suggest that EEPL is effective therapeutic candidate that can be used to prevent or treat postmenopausal osteoporosis.
Asunto(s)
Osteoclastos/efectos de los fármacos , Extractos Vegetales/farmacología , Polypodiaceae , Ligando RANK/efectos de los fármacos , Animales , Hueso Esponjoso/efectos de los fármacos , Línea Celular , Modelos Animales de Enfermedad , Femenino , Ratones , Ratones Endogámicos C57BL , Proteínas Quinasas Activadas por Mitógenos/efectos de los fármacos , FN-kappa B/efectos de los fármacos , Osteoporosis/patología , Ovariectomía , Proteínas Proto-Oncogénicas c-fos/efectos de los fármacos , Receptores de Hidrocarburo de Aril/efectos de los fármacos , Aumento de Peso/efectos de los fármacosRESUMEN
Background: Monochromatic blue light (MBL), with a wavelength between 400-490 nm, can regulate non-image-forming (NIF) functions of light in the central nervous system. The suprachiasmatic nucleus (SCN) in the brain is involved in the arousal-promoting response to blue light in mice. Animal and human studies showed that the responsiveness of the brain to visual stimuli is partly preserved under general anesthesia. Therefore, this study aimed to investigate whether MBL promotes arousal from sevoflurane anesthesia via activation of the SCN in mice. Methods: The induction and emergence time of sevoflurane anesthesia under MBL (460 nm and 800 lux) exposure was measured. Cortical electroencephalograms (EEGs) were recorded and the burst-suppression ratio (BSR) was calculated under MBL during sevoflurane anesthesia. The EEGs and local field potential (LFP) recordings with or without locally electrolytic ablated bilateral SCN were used to further explore the role of SCN in the arousal-promoting effect of MBL under sevoflurane anesthesia. Immunofluorescent staining of c-Fos was conducted to reveal the possible downstream mechanism of SCN activation. Results: Unlike the lack of effect on the induction time, MBL shortened the emergence time and the EEG recordings showed cortical arousal during the recovery period. MBL resulted in a significant decrease in BSR and a marked increase in EEG power at all frequency bands except for the spindle band during 2.5% sevoflurane anesthesia. MBL exposure under sevoflurane anesthesia enhances the neuronal activity of the SCN. These responses to MBL were abolished in SCN lesioned (SCNx) mice. MBL evoked a high level of c-Fos expression in the prefrontal cortex (PFC) and lateral hypothalamus (LH) compared to polychromatic white light (PWL) under sevoflurane anesthesia, while it exerted no effect on c-Fos expression in the ventrolateral preoptic area (VLPO) and locus coeruleus (LC) c-Fos expression. Conclusions: MBL promotes behavioral and electroencephalographic arousal from sevoflurane anesthesia via the activation of the SCN and its associated downstream wake-related nuclei. The clinical implications of this study warrant further study.
Asunto(s)
Anestésicos por Inhalación/farmacología , Nivel de Alerta/efectos de la radiación , Hipotálamo/efectos de la radiación , Luz , Neuronas/efectos de la radiación , Corteza Prefrontal/efectos de la radiación , Sevoflurano/farmacología , Núcleo Supraquiasmático/efectos de la radiación , Anestesia , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/efectos de la radiación , Electroencefalografía , Hipotálamo/efectos de los fármacos , Hipotálamo/metabolismo , Ratones , Neuronas/efectos de los fármacos , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/metabolismo , Proteínas Proto-Oncogénicas c-fos/efectos de los fármacos , Proteínas Proto-Oncogénicas c-fos/metabolismo , Proteínas Proto-Oncogénicas c-fos/efectos de la radiación , Reflejo de Enderezamiento/efectos de los fármacos , Reflejo de Enderezamiento/efectos de la radiación , Núcleo Supraquiasmático/citología , Núcleo Supraquiasmático/efectos de los fármacos , Núcleo Supraquiasmático/metabolismoRESUMEN
OBJECTIVE: To study the effects of Zuogui Jiangtang Jieyu Formula (ZGJTJYF, the Chinese Medicine) on hippocampal neuron apoptosis in diabetes mellitus complicated with depression (DD). METHODS: The primary cultured hippocampal neurons were treated with high glucose (150 mmol/L) and corticosterone (200 micromol/L) to establish the cell model of DD in vitro. The cultured hippocampal neurons were randomly divided into five groups: blank serum group, normal group, Zuogui Jiangtang Jieyu recipe drug-containing serum group, positive drug (metformin + fluoxetine) drug-containing serum group and model group (three compound holes in each group). The model group and the normal group were given the same amount of culture medium, and the other groups were given the corresponding serum with 10% volume fraction for 18 hours. Hoechst staining, high content cell imaging and RT-PCR were used to detect the apoptosis of hippocampal neurons and the expressions of apoptosis-related ETS-like 1 transcription factor(ELK-1), C-Jun N-terminal kinase(JNK) and c-Fos proteins and genes. RESULTS: Compared with the blank group, the apoptotic number of hippocampal neurons in the model group was increased significantly, and the expression levels of ELK-1, JNK and c-Fos were increased significantly (Pï¼0.05). Compared with the model group, the local bright spots of hippocampal neurons in the Zuogui Jiangtang Jieyu recipe-containing serum group and the positive drug-containing serum group were decreased significantly, and the number of apoptotic cells was decreased significantly. The expressions of JNK, c-fos protein and mRNA were down-regulated significantly (Pï¼ 0.05), and the neural network and dendritic junction were improved significantly. CONCLUSION: Zuo Gui Jiang Tang Jie Yu Formula can reverse the expressions of ELK-1, JNK and c-Fos signals in hippocampal neurons under DD environment and play an anti-apoptotic effect.
Asunto(s)
Depresión , Complicaciones de la Diabetes , Diabetes Mellitus , Medicamentos Herbarios Chinos , Hipocampo , Animales , Apoptosis/efectos de los fármacos , Depresión/tratamiento farmacológico , Complicaciones de la Diabetes/tratamiento farmacológico , Medicamentos Herbarios Chinos/farmacología , Hipocampo/efectos de los fármacos , MAP Quinasa Quinasa 4/efectos de los fármacos , Neuronas , Proteínas Proto-Oncogénicas c-fos/efectos de los fármacos , Distribución Aleatoria , Ratas , Proteína Elk-1 con Dominio ets/efectos de los fármacosRESUMEN
Light synchronizes the body's circadian rhythms by modulating the master clock located in the suprachiasmatic nucleus (SCN) of the hypothalamus. In modern lifestyles that run counter to normal circadian rhythms, the extended and/or irregular light exposure impairs circadian rhythms and, consequently, promotes feeding and metabolic disorders. However, the neuronal pathway through which light is coupled to feeding behavior is less elucidated. The present study employed the light exposure during the dark phase of the day in rats and observed its effect on neuronal activity and feeding behavior. Light exposure acutely suppressed food intake and elevated c-Fos expression in the AVP neurons of SCN and the oxytocin (Oxt) neurons of paraventricular nucleus (PVN) in the hypothalamus. The light-induced suppression of food intake was abolished by blockade of the Oxt receptor in the brain. Retrograde tracer analysis demonstrated the projection of SCN AVP neurons to the PVN. Furthermore, intracerebroventricular injection of AVP suppressed food intake and increased c-Fos in PVN Oxt neurons. Intra-PVN injection of AVP exerted a stronger anorexigenic effect than intracerebroventriclar injection. AVP also induced intracellular Ca2+ signaling and increased firing frequency in Oxt neurons in PVN slices. These results reveal the novel neurocircuit from SCN AVP to PVN Oxt that relays light reception to inhibition of feeding behavior. This light-induced neurocircuit may serve as a pathway for forming the circadian feeding rhythm and linking irregular light exposure to arrhythmic feeding and, consequently, obesity and metabolic diseases.
Asunto(s)
Arginina Vasopresina/metabolismo , Conducta Alimentaria/fisiología , Luz , Oxitocina/metabolismo , Núcleo Hipotalámico Paraventricular/metabolismo , Núcleo Supraquiasmático/metabolismo , Animales , Arginina Vasopresina/farmacología , Arginina Vasopresina/fisiología , Señalización del Calcio/efectos de los fármacos , Señalización del Calcio/fisiología , Ritmo Circadiano/fisiología , Conducta Alimentaria/efectos de los fármacos , Hipotálamo/metabolismo , Hipotálamo/fisiología , Inhibición Psicológica , Masculino , Vías Nerviosas , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Oxitocina/fisiología , Núcleo Hipotalámico Paraventricular/fisiología , Proteínas Proto-Oncogénicas c-fos/efectos de los fármacos , Proteínas Proto-Oncogénicas c-fos/metabolismo , Ratas , Ratas Wistar , Receptores de Oxitocina , Núcleo Supraquiasmático/fisiologíaRESUMEN
Pharmacological ß3-adrenergic receptor (ß3AR) activation leads to increased mitochondrial biogenesis and activity in white adipose tissue (WAT), a process commonly referred to as "browning", and transiently increased insulin release. These effects are associated with improved metabolic function and weight loss. It is assumed that this impact of ß3AR agonists is mediated solely through activation of ß3ARs in adipose tissue. However, ß3ARs are also found in the brain, in areas such as the brain stem and the hypothalamus, which provide multisynaptic innervation to brown and white adipose depots. Thus, contrary to the current adipocentric view, the central nervous system (CNS) may also have the ability to regulate energy balance and metabolism through actions on central ß3ARs. Therefore, this study aimed to elucidate whether CNS ß3ARs can regulate browning of WAT and other aspects of metabolic regulation, such as food intake control and insulin release. We found that acute central injection of ß3AR agonist potently reduced food intake, body weight, and increased hypothalamic neuronal activity in rats. Acute central ß3AR stimulation was also accompanied by a transient increase in circulating insulin levels. Moreover, subchronic central ß3AR agonist treatment led to a browning response in both inguinal (IWAT) and gonadal WAT (GWAT), along with reduced GWAT and increased BAT mass. In high-fat, high-sugar-fed rats, subchronic central ß3AR stimulation reduced body weight, chow, lard, and sucrose water intake, in addition to increasing browning of IWAT and GWAT. Collectively, our results identify the brain as a new site of action for the anorexic and browning impact of ß3AR activation.
Asunto(s)
Tejido Adiposo Pardo/efectos de los fármacos , Tejido Adiposo Blanco/efectos de los fármacos , Agonistas de Receptores Adrenérgicos beta 3/farmacología , Antagonistas de Receptores Adrenérgicos beta 3/farmacología , Peso Corporal/efectos de los fármacos , Dioxoles/farmacología , Conducta Alimentaria/efectos de los fármacos , Propanolaminas/farmacología , Receptores Adrenérgicos beta 3/efectos de los fármacos , Animales , Línea Celular , Sistema Nervioso Central , Dieta Alta en Grasa , Metabolismo Energético/efectos de los fármacos , Perfilación de la Expresión Génica , Hipotálamo/citología , Hipotálamo/efectos de los fármacos , Hipotálamo/metabolismo , Inmunohistoquímica , Insulina/metabolismo , Secreción de Insulina , Yoduro Peroxidasa/genética , Masculino , Neuronas/citología , Neuronas/efectos de los fármacos , Proteínas Proto-Oncogénicas c-fos/efectos de los fármacos , Proteínas Proto-Oncogénicas c-fos/metabolismo , Ratas , Ratas Sprague-Dawley , Factores de Transcripción/genética , Proteína Desacopladora 1/genética , Yodotironina Deyodinasa Tipo IIRESUMEN
ABSTRACT Tryptophan is the only precursor of serotonin and mediates serotonergic activity in the brain. Previous studies have shown that the administration of tryptophan or tryptophan depletion significantly alters cognition, mood and anxiety. Nevertheless, the neurobiological alterations that follow these changes have not yet been fully investigated. The aim of this study was to verify the effects of a tryptophan-enriched diet on immunoreactivity to Fos-protein in the rat brain. Sixteen male Wistar rats were distributed into two groups that either received standard chow diet or a tryptophan-enriched diet for a period of thirty days. On the morning of the 31st day, animals were euthanized and subsequently analyzed for Fos-immunoreactivity (Fos-ir) in the dorsal and median raphe nuclei and in regions that receive serotonin innervation from these two brain areas. Treatment with a tryptophan-enriched diet increased Fos-ir in the prefrontal cortex, nucleus accumbens, paraventricular hypothalamus, arcuate and ventromedial hypothalamus, dorsolateral and dorsomedial periaqueductal grey and dorsal and median raphe nucleus. These observations suggest that the physiological and behavioral alterations that follow the administration of tryptophan are associated with the activation of brain regions that regulate cognition and mood/anxiety-related responses.
Asunto(s)
Animales , Masculino , Ansiedad/tratamiento farmacológico , Encéfalo/efectos de los fármacos , Proteínas Proto-Oncogénicas c-fos/efectos de los fármacos , Cognición/efectos de los fármacos , Antidepresivos de Segunda Generación/administración & dosificación , Afecto/efectos de los fármacos , Ansiedad/metabolismo , Factores de Tiempo , Triptófano/administración & dosificación , Encéfalo/metabolismo , Inmunohistoquímica , Serotonina/metabolismo , Reproducibilidad de los Resultados , Resultado del Tratamiento , Proteínas Proto-Oncogénicas c-fos/metabolismo , Ratas Wistar , Suplementos Dietéticos , Dietoterapia/métodosRESUMEN
Tryptophan is the only precursor of serotonin and mediates serotonergic activity in the brain. Previous studies have shown that the administration of tryptophan or tryptophan depletion significantly alters cognition, mood and anxiety. Nevertheless, the neurobiological alterations that follow these changes have not yet been fully investigated. The aim of this study was to verify the effects of a tryptophan-enriched diet on immunoreactivity to Fos-protein in the rat brain. Sixteen male Wistar rats were distributed into two groups that either received standard chow diet or a tryptophan-enriched diet for a period of thirty days. On the morning of the 31st day, animals were euthanized and subsequently analyzed for Fos-immunoreactivity (Fos-ir) in the dorsal and median raphe nuclei and in regions that receive serotonin innervation from these two brain areas. Treatment with a tryptophan-enriched diet increased Fos-ir in the prefrontal cortex, nucleus accumbens, paraventricular hypothalamus, arcuate and ventromedial hypothalamus, dorsolateral and dorsomedial periaqueductal grey and dorsal and median raphe nucleus. These observations suggest that the physiological and behavioral alterations that follow the administration of tryptophan are associated with the activation of brain regions that regulate cognition and mood/anxiety-related responses.
Asunto(s)
Afecto/efectos de los fármacos , Antidepresivos de Segunda Generación/administración & dosificación , Ansiedad/tratamiento farmacológico , Encéfalo/efectos de los fármacos , Cognición/efectos de los fármacos , Proteínas Proto-Oncogénicas c-fos/efectos de los fármacos , Triptófano/administración & dosificación , Animales , Ansiedad/metabolismo , Encéfalo/metabolismo , Dietoterapia/métodos , Suplementos Dietéticos , Inmunohistoquímica , Masculino , Proteínas Proto-Oncogénicas c-fos/metabolismo , Ratas Wistar , Reproducibilidad de los Resultados , Serotonina/metabolismo , Factores de Tiempo , Resultado del TratamientoRESUMEN
Type 2 diabetes (T2D) is among the most common and costly disorders worldwide. The goal of current medical management for T2D is to transiently ameliorate hyperglycemia through daily dosing of one or more antidiabetic drugs. Hypoglycemia and weight gain are common side effects of therapy, and sustained disease remission is not obtainable with nonsurgical approaches. On the basis of the potent glucose-lowering response elicited by activation of brain fibroblast growth factor (FGF) receptors, we explored the antidiabetic efficacy of centrally administered FGF1, which, unlike other FGF peptides, activates all FGF receptor subtypes. We report that a single intracerebroventricular injection of FGF1 at a dose one-tenth of that needed for antidiabetic efficacy following peripheral injection induces sustained diabetes remission in both mouse and rat models of T2D. This antidiabetic effect is not secondary to weight loss, does not increase the risk of hypoglycemia, and involves a novel and incompletely understood mechanism for increasing glucose clearance from the bloodstream. We conclude that the brain has an inherent potential to induce diabetes remission and that brain FGF receptors are potential pharmacological targets for achieving this goal.
Asunto(s)
Glucemia/efectos de los fármacos , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Factor 1 de Crecimiento de Fibroblastos/farmacología , Tejido Adiposo/efectos de los fármacos , Tejido Adiposo/metabolismo , Animales , Glucemia/metabolismo , Western Blotting , Composición Corporal , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Radioisótopos de Carbono , Desoxiglucosa , Dieta Alta en Grasa , Modelos Animales de Enfermedad , Células Ependimogliales/efectos de los fármacos , Células Ependimogliales/metabolismo , Proteína Forkhead Box O1/genética , Prueba de Tolerancia a la Glucosa , Corazón/efectos de los fármacos , Proteínas de Choque Térmico/efectos de los fármacos , Proteínas de Choque Térmico/metabolismo , Hiperglucemia/metabolismo , Hipotálamo/citología , Hipotálamo/efectos de los fármacos , Hipotálamo/metabolismo , Inyecciones Intraventriculares , Hígado/metabolismo , Masculino , Ratones , Ratones Noqueados , Ratones Obesos , Chaperonas Moleculares , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/metabolismo , Miocardio/metabolismo , Proteínas de Neoplasias/efectos de los fármacos , Proteínas de Neoplasias/metabolismo , Proteínas Proto-Oncogénicas c-fos/efectos de los fármacos , Proteínas Proto-Oncogénicas c-fos/metabolismo , Ratas , Ratas Zucker , Reacción en Cadena en Tiempo Real de la Polimerasa , Receptor de Insulina/antagonistas & inhibidores , Receptor de Insulina/genética , Inducción de RemisiónRESUMEN
Formononetin (1), a plant-derived phytoestrogen, possesses bone protective properties. To address the potential therapeutic efficacy and mechanism of action of 1, we investigated its antiosteoclastogenic activity and its effect on nuclear factor-kappaB ligand (RANKL)-induced bone-marrow-derived macrophages (BMMs). Compound 1 markedly inhibited RANKL-induced osteoclast differentiation in the absence of cytotoxicity, by regulating the expression of osteoprotegerin (OPG) and RANKL in BMMs and in cocultured osteoblasts. Compound 1 significantly inhibited RANKL-induced tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, IL-6, monocyte chemoattractant protein-1 (MCP-1), regulated on activation normal T cell expressed and secreted (RANTES), and macrophage inflammatory protein-1α (MIP-1α) in a concentration-dependent manner. These effects were accompanied by a decrease in RANKL-induced activation of the NF-κB p65 subunit, degradation of inhibitor κBα (IκBα), induction of NF-κB, and phosphorylation of AKT, extracellular-signal regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38 mitogen-activated protein kinase (p38 MAPK). NF-κB siRNA suppressed AKT, ERK, JNK, and p38 MAPK phosphorylation. Furthermore, 1 significantly suppressed c-Fos and nuclear factor of activated T-cells cytoplasmic 1 (NFATc1), key transcription factors during osteoclastogenesis. SP600125, a specific inhibitor of JNK, reduced RANKL-induced expression of phospho-c-Jun, c-Fos, and NFATc1 and inhibited osteoclast formation. These results suggested that 1 acted as an antiresorption agent by blocking osteoclast activation.
Asunto(s)
Isoflavonas/farmacología , FN-kappa B/antagonistas & inhibidores , Fitoestrógenos/farmacología , Quimiocina CCL2 , Interleucina-6/metabolismo , Isoflavonas/química , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Macrófagos/efectos de los fármacos , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Estructura Molecular , Osteoblastos/efectos de los fármacos , Osteoclastos/efectos de los fármacos , Fitoestrógenos/química , Proteínas Proto-Oncogénicas c-fos/efectos de los fármacos , Ligando RANK/farmacología , Transducción de Señal/efectos de los fármacos , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
This study first showed the behavioural benefits of novel combination therapy of L-dopa with acupuncture on Parkinson's disease, and its underlying mechanisms within basal ganglia. The previous study reported that acupuncture may improve the motor function of a Parkinson's disease (PD) mouse model by increasing the dopamine efflux and turnover ratio of dopamine. Hence, we hypothesised that combining L-dopa with acupuncture would have a behavioural benefit for those with PD. We performed unilateral injections of 6-OHDA into the striatum of C57Bl/6 mice to model hemi-Parkinsonian attributes. To test motor function and dyskinetic anomalies, we examined cylinder behaviour and abnormal involuntary movement (AIM), respectively. We found that (1) a 50% reduced dose of L-dopa (7.5 mg/kg) combined with acupuncture showed an improvement in motor function that was comparable to mice given the standard dose of L-dopa treatment (15 mg/kg) only, and that (2) the combination treatment (L-dopa +acupuncture) was significantly superior in reducing AIM scores when equivalent doses of L-dopa were used. The combination treatment also significantly reduces the abnormal increase of GABA contents in the substantia nigra compared to the standard L-dopa treatment. Furthermore, abnormal expression of FosB, the immediate early gene of L-dopa induced dyskinesia (LID), was mitigated in the striatum by the combination treatment. All of these results indicate that acupuncture enhances the benefits of L-dopa on motor function with reduced dose of L-dopa and alleviating LID by normalising neurochemical imbalance within the basal ganglia.
Asunto(s)
Terapia por Acupuntura , Antiparkinsonianos/efectos adversos , Química Encefálica , Levodopa/efectos adversos , Enfermedad de Parkinson Secundaria/terapia , Animales , Terapia Combinada , Ácido Glutámico/análisis , Masculino , Ratones , Ratones Endogámicos C57BL , Movimiento/efectos de los fármacos , Oxidopamina/toxicidad , Enfermedad de Parkinson Secundaria/inducido químicamente , Proteínas Proto-Oncogénicas c-fos/efectos de los fármacos , Proteínas Proto-Oncogénicas c-fos/metabolismo , Sustancia Negra/química , Ácido gamma-Aminobutírico/análisisRESUMEN
Sex differences in the spinal processing of somatic and visceral stimuli contribute to greater female sensitivity in many pain disorders. The present study examined spinal mechanisms that contribute to sex differences in visceral sensitivity. The visceromotor response to colorectal distention (CRD) was more robust in normal female rats and after intracolonic mustard oil compared with that in male rats. No sex difference was observed in the CRD-evoked response of lumbosacral (LS) and thoracolumbar (TL) colonic afferents in normal and mustard oil-treated rats, but there was a sex difference in spontaneous activity that was exacerbated by intracolonic mustard oil. The response of visceroceptive dorsal horn neurons to CRD was greater in normal female rats in the LS and TL spinal segments. The effect of intracolonic mustard oil on the CRD-evoked response of different phenotypes of visceroceptive dorsal horn neurons was dependent on sex and segment. The NMDA receptor antagonist 2-amino-5-phosphonopentanoic acid (APV) dose-dependently attenuated the visceromotor response in normal rats with greater effect in male rats. Correspondingly, there was greater cell membrane expression of the GluN1 subunit in dorsal horn extracts in female rats. After intracolonic mustard oil, there was no longer a sex difference in the effect of APV nor GluN1 expression in LS segments, but greater female expression in TL segments. These data document a sex difference in spinal processing of nociceptive visceral stimuli from the normal and inflamed colon. Differences in dorsal horn neuronal activity and NMDA receptor expression contribute to the sex differences in the visceral sensitivity observed in awake rats.
Asunto(s)
Nocicepción/fisiología , Células del Asta Posterior/fisiología , Receptores de N-Metil-D-Aspartato/metabolismo , Aferentes Viscerales/fisiología , Dolor Visceral/fisiopatología , 2-Amino-5-fosfonovalerato/farmacología , Animales , Colon/efectos de los fármacos , Colon/inervación , Colon/fisiología , Electromiografía , Femenino , Irritantes/farmacología , Masculino , Planta de la Mostaza , Nocicepción/efectos de los fármacos , Aceites de Plantas/farmacología , Células del Asta Posterior/efectos de los fármacos , Células del Asta Posterior/metabolismo , Proteínas Proto-Oncogénicas c-fos/efectos de los fármacos , Proteínas Proto-Oncogénicas c-fos/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Receptores de N-Metil-D-Aspartato/efectos de los fármacos , Factores Sexuales , Médula Espinal/efectos de los fármacos , Médula Espinal/metabolismo , Médula Espinal/fisiología , Aferentes Viscerales/efectos de los fármacos , Aferentes Viscerales/metabolismo , Dolor Visceral/metabolismoRESUMEN
Proliferation of vascular smooth muscle cells (VSMCs) is a crucial event in cardiovascular diseases. Isorhynchophylline, an alkaloid from a traditional Chinese medicine Gambirplant, has been used to treat cardiovascular diseases. The aim of this study was to investigate the effects of isorhynchophylline on angiotensin II (Ang II)-induced proliferation of rat VSMCs. VSMCs were isolated from rat artery and cultured for 14 days before experimentation. The effect of isorhynchophylline on Ang II-induced proliferation was evaluated by cell number, MTT assay and flow cytometry, and nitric oxide (NO) content and activity of NO synthase (NOS) were measured. The expression of proto-oncogene c-fos, osteopontin (OPN) and proliferating cell nuclear antigen (PCNA) mRNAs was measured by real-time RT-PCR. VSMC cultures were verified by morphology and immunostaining with alpha-smooth muscle actin. Isorhynchophylline (0.1-10.0 microM) was not toxic to VSMCs, but markedly decreased Ang II (1.0 microM)-enhanced cell number and MTT intensity, and blocked cell transition from G(0)/G(1) to S phase. Furthermore, isorhynchophylline increased the NO content and NOS activity, and suppressed Ang II-induced over-expression of c-fos, OPN and PCNA. Thus, isorhynchophylline was effective against Ang-II induced cell proliferation, an effect that appears to be due, at least in part, to increased NO production, regulation of the cell cycle, and depressed expression of c-fos, OPN and PCNA related to VMSC proliferation.
Asunto(s)
Angiotensina II/metabolismo , Proliferación Celular/efectos de los fármacos , Alcaloides Indólicos/farmacología , Óxido Nítrico/metabolismo , Animales , Ciclo Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Medicamentos Herbarios Chinos/administración & dosificación , Medicamentos Herbarios Chinos/efectos adversos , Medicamentos Herbarios Chinos/farmacología , Citometría de Flujo , Regulación de la Expresión Génica/efectos de los fármacos , Alcaloides Indólicos/administración & dosificación , Alcaloides Indólicos/efectos adversos , Masculino , Músculo Liso Vascular/citología , Músculo Liso Vascular/efectos de los fármacos , Músculo Liso Vascular/metabolismo , Miocitos del Músculo Liso/efectos de los fármacos , Miocitos del Músculo Liso/metabolismo , Osteopontina/efectos de los fármacos , Osteopontina/metabolismo , Oxindoles , Antígeno Nuclear de Célula en Proliferación/efectos de los fármacos , Antígeno Nuclear de Célula en Proliferación/metabolismo , Proteínas Proto-Oncogénicas c-fos/efectos de los fármacos , Proteínas Proto-Oncogénicas c-fos/metabolismo , Ratas , Ratas Sprague-Dawley , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
Sickness behaviour is an adaptive behavioural response to the activation of the innate immune system. It is mediated by brain cytokine production and action, especially interleukin-6 (IL-6). Polyunsaturated fatty acids (PUFA) are essential fatty acids that are highly incorporated in brain cell membranes and display immunomodulating properties. We hypothesized that a decrease in n-3 (also known as omega3) PUFA brain level by dietary means impacts on lipopolysaccharide (LPS)-induced IL-6 production and sickness behaviour. Our results show that mice exposed throughout life to a diet containing n-3 PUFA (n-3/n-6 diet) display a decrease in social interaction that does not occur in mice submitted to a diet devoid of n-3 PUFA (n-6 diet). LPS induced high IL-6 plasma levels as well as expression of IL-6 mRNA in the hippocampus and cFos mRNA in the brainstem of mice fed either diet, indicating intact immune-to-brain communication. However, STAT3 and STAT1 activation, a hallmark of the IL-6 signalling pathway, was lower in the hippocampus of LPS-treated n-6 mice than n-3/n-6 mice. In addition, LPS did not reduce social interaction in IL-6-knockout (IL-6-KO) mice and failed to induce STAT3 activation in the brain of IL-6-KO mice. Altogether, these findings point to alteration in brain STAT3 as a key mechanism for the lack of effect of LPS on social interaction in mice fed with the n-6 PUFA diet. The relative deficiency of Western diets in n-3 PUFA could impact on behavioural aspects of the host response to infection.
Asunto(s)
Encéfalo/metabolismo , Grasas Insaturadas en la Dieta/metabolismo , Ácidos Grasos Omega-3/metabolismo , Conducta de Enfermedad/fisiología , Interleucina-6/metabolismo , Factor de Transcripción STAT3/metabolismo , Animales , Conducta Animal/fisiología , Encéfalo/inmunología , Encéfalo/fisiopatología , Tronco Encefálico/inmunología , Tronco Encefálico/metabolismo , Tronco Encefálico/fisiopatología , Femenino , Hipocampo/inmunología , Hipocampo/metabolismo , Hipocampo/fisiopatología , Inmunidad Innata/genética , Inmunidad Innata/inmunología , Interleucina-6/genética , Interleucina-6/inmunología , Lipopolisacáridos/farmacología , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos ICR , Ratones Noqueados , Proteínas Proto-Oncogénicas c-fos/efectos de los fármacos , Proteínas Proto-Oncogénicas c-fos/genética , Proteínas Proto-Oncogénicas c-fos/metabolismo , ARN Mensajero/efectos de los fármacos , ARN Mensajero/metabolismo , Factor de Transcripción STAT3/genética , Factor de Transcripción STAT3/inmunología , Conducta SocialRESUMEN
The behavioral profile in response to (+/-)-3,4-methylenedioxymethamphetamine (MDMA) is characterized by acute hyperlocomotion that is primarily restricted to the periphery of the open field, whereas behavioral sensitization to MDMA reflects a selective increase in activity in the central zone, suggesting that acute effects and sensitization might rely on neuroadaptations in different systems. This study was thus undertaken to determine whether specific changes in neuronal activation could be correlated with either the acute or sensitized behavioral responses to MDMA. Animals received five daily intraperitoneal (i.p.) injections of saline or MDMA (10 mg/kg). Two days later, animals that received saline were injected with saline or MDMA (5 or 10 mg/kg, i.p.). Animals pretreated with MDMA were injected with saline or MDMA (5 mg/kg, i.p.). Locomotor activity was measured in an open field, and neuronal activation was examined by immunodetection of Fos. Acute MDMA exposure produced a dose-dependent increase in locomotion in the peripheral zone of the open field that was related to an increase in Fos expression in the ventromedial shell of the nucleus accumbens, ventral pallidum, several hypothalamic nuclei and rhomboid thalamic nucleus. Following repeated, intermittent exposure to MDMA, drug-produced hyperactivity became sensitized but, unlike the effect of increasing dose, the increased response was due to increased activity and time spent in the central zone. Furthermore, the sensitized behavioral response was related to changes in Fos expression in the lateral shell of the nucleus accumbens, central nucleus of the amygdala and anteromedial part of the lateral habenula. This study identifies neural substrates that might specifically underlie the sensitized response to MDMA.
Asunto(s)
Encéfalo/efectos de los fármacos , N-Metil-3,4-metilenodioxianfetamina/farmacología , Proteínas Proto-Oncogénicas c-fos/efectos de los fármacos , Amígdala del Cerebelo/efectos de los fármacos , Amígdala del Cerebelo/metabolismo , Animales , Ganglios Basales/efectos de los fármacos , Ganglios Basales/metabolismo , Conducta Animal/efectos de los fármacos , Conducta Animal/fisiología , Encéfalo/anatomía & histología , Encéfalo/metabolismo , Mapeo Encefálico , Relación Dosis-Respuesta a Droga , Resistencia a Medicamentos/efectos de los fármacos , Resistencia a Medicamentos/fisiología , Habénula/efectos de los fármacos , Habénula/metabolismo , Alucinógenos/farmacología , Hipotálamo/efectos de los fármacos , Hipotálamo/metabolismo , Inmunohistoquímica , Masculino , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiología , Núcleo Accumbens/efectos de los fármacos , Núcleo Accumbens/metabolismo , Proteínas Proto-Oncogénicas c-fos/metabolismo , Agitación Psicomotora/fisiopatología , Ratas , Ratas Sprague-DawleyRESUMEN
The central mechanisms that mediate neuropeptide K (NPK) associated anorexia are poorly understood in any species, and information in this area of avian biology is totally lacking. Thus, the effects of intracerebroventricular NPK treatment were studied in Cobb-500 chicks (Gallus gallus). In Experiment 1, NPK caused decreased feed intake, but did not affect water intake or whole blood glucose concentration. In Experiment 2, NPK-treated chicks had increased c-Fos immunoreactivity in the parvicellular division of the paraventricular nucleus and arcuate nucleus. The lateral hypothalamus, ventromedial hypothalamus, dorsomedial hypothalamus, periventricular nucleus, magnocellular division of the paraventricular nucleus, and the superchiasmatic nucleus were not affected by NPK treatment. In Experiment 3, the number of feed pecks, exploratory pecks, jumps, escape attempts, and distance moved were decreased, while time spent standing was increased. None of the NPK-treated chicks sat or entered deep rest. In Experiment 4, blockage of corticotrophin releasing factor receptors did not affect NPK-induced anorexia. Thus, we conclude that NPK is a regulator of chick appetite and the effects may be mediated directly in the arcuate nucleus and parvicellular division of the paraventricular nucleus.
Asunto(s)
Pollos/metabolismo , Ingestión de Alimentos/efectos de los fármacos , Hipotálamo/fisiología , Taquicininas/farmacología , Animales , Conducta Animal/efectos de los fármacos , Glucemia/efectos de los fármacos , Hormona Liberadora de Corticotropina/farmacología , Relación Dosis-Respuesta a Droga , Ingestión de Líquidos/efectos de los fármacos , Inyecciones Intraventriculares , Fragmentos de Péptidos/farmacología , Proteínas Proto-Oncogénicas c-fos/análisis , Proteínas Proto-Oncogénicas c-fos/efectos de los fármacos , Distribución Aleatoria , Receptores de Hormona Liberadora de Corticotropina/antagonistas & inhibidores , Receptores de Hormona Liberadora de Corticotropina/efectos de los fármacos , Taquicininas/administración & dosificaciónRESUMEN
Effects of the direct NMDA agonist (tetrazol-5-yl)glycine (TZG) were examined in a genetic mouse model of reduced NMDA receptor function. In this model, expression of the NR1 subunit is reduced but not eliminated and the mice are therefore designated as NR1 hypomorphic. Previous work suggested that the reduced NR1 subunit expression produced a functional subsensitivity as judged by a blunted Fos induction response to a sub-seizure dose of TZG. In the present study seizure threshold doses of TZG were tested in the wild type and mutant mice. Surprisingly, there was no difference in the seizure sensitivity between the wild type mice and mice presumed to express very low levels of the NR1 subunit. An extensive neuroanatomical analysis of Fos induction was conducted after the threshold seizure doses of TZG. The results demonstrate that some brain regions of the NR1 -/- mice exhibit much lower Fos induction in comparison to the NR1 +/+ mice. These regions include hippocampus, amygdala, and cerebral cortical regions. However, in other regions, similar induction of Fos was observed in both genotypes in response to the NMDA agonist. Regions showing similar Fos induction in the NR1 +/+ and NR1 -/- mice include the lateral septum, nucleus of the solitary tract, and medial hypothalamic regions. The results suggest that the NMDA receptor hypofunction in the NR1 -/- mice is not global but regionally specific and that subcortical structures are responsible for the seizure-inducing effects of TZG.
Asunto(s)
Encéfalo/metabolismo , Proteínas Proto-Oncogénicas c-fos/metabolismo , Receptores de N-Metil-D-Aspartato/genética , Convulsiones/metabolismo , Animales , Encéfalo/efectos de los fármacos , Encéfalo/fisiopatología , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Resistencia a Medicamentos/genética , Agonistas de Aminoácidos Excitadores/farmacología , Femenino , Predisposición Genética a la Enfermedad/genética , Ácido Glutámico/metabolismo , Glicina/análogos & derivados , Glicina/farmacología , Hipotálamo/efectos de los fármacos , Hipotálamo/metabolismo , Hipotálamo/fisiopatología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas Proto-Oncogénicas c-fos/efectos de los fármacos , Receptores de N-Metil-D-Aspartato/agonistas , Convulsiones/inducido químicamente , Convulsiones/genética , Núcleos Septales/efectos de los fármacos , Núcleos Septales/metabolismo , Núcleos Septales/fisiopatología , Núcleo Solitario/efectos de los fármacos , Núcleo Solitario/metabolismo , Núcleo Solitario/fisiopatología , Transmisión Sináptica/efectos de los fármacos , Transmisión Sináptica/genética , Tetrazoles/farmacologíaRESUMEN
Several peptides that are derived from proglucagon including glucagon, glucagon-like peptide-1 (GLP-1), and oxyntomodulin (OXM) cause satiety in mammals. Glucagon and GLP-1 also cause satiety in the avian, but the effects of OXM on avian appetite-related processes are not reported. Thus, this study was conducted to elucidate whether OXM induces satiety in chicks and to determine its mechanism of induction. Intracerebroventricular (ICV) OXM, in a linear-dose dependent manner, potently decreased feed and water intake. However, we found that the effect on water intake was secondary to a reduction in feed intake. Chicks treated with ICV OXM had decreased c-Fos immunoreactivity in the regio lateralis hypothalami, but the nucleus infundibuli hypothalami (homologue to the mammalian arcuate nucleus) had increased c-Fos immunoreactivity. ICV OXM also caused total alimentary canal transit time to be decreased. We conclude that changes in the hypothalamus and gut may contribute to anorexigenic effects after ICV OXM in chicks. Through divergent evolution of birds and mammals, the central anorexigenic effects of OXM may have been conserved.
Asunto(s)
Anorexia/fisiopatología , Anorexia/veterinaria , Pollos/metabolismo , Sistema Digestivo/fisiopatología , Hipotálamo/metabolismo , Oxintomodulina/efectos adversos , Alimentación Animal , Fenómenos Fisiológicos Nutricionales de los Animales/efectos de los fármacos , Animales , Anorexia/inducido químicamente , Depresores del Apetito/administración & dosificación , Depresores del Apetito/efectos adversos , Regulación del Apetito/efectos de los fármacos , Ingestión de Líquidos/efectos de los fármacos , Tránsito Gastrointestinal/efectos de los fármacos , Inyecciones , Oxintomodulina/administración & dosificación , Proteínas Proto-Oncogénicas c-fos/efectos de los fármacos , Proteínas Proto-Oncogénicas c-fos/genética , Respuesta de Saciedad/efectos de los fármacosRESUMEN
In Syrian hamsters, some procedures for stimulating behavioural arousal (e.g. running in a novel wheel and sleep deprivation by gentle handling with minimal activity) markedly phase-advance circadian rhythms when applied during the middle of the daily rest period, while other arousal procedures do not (e.g. physical restraint, caffeine and modafinil). The neural basis for this differential effect of arousal procedures on clock resetting is unknown. We used c-fos expression as a marker for neuronal activation to determine whether these arousal procedures differentially activate two nonphotic inputs to the circadian system, the thalamic intergeniculate leaflet (IGL; a proposed nonphotic gateway to the circadian clock) and the hypothalamic hypocretin system (which depolarizes arousal-related cell groups throughout the brain and innervates both the IGL and the peri-suprachiasmatic nucleus region). c-FOS in hypocretin-1-immunoreactive neurons, in hypothalamic nonhypocretin neurons and in the IGL was significantly increased by novel wheel running, gentle handling and physical restraint, but only weakly by systemic injections of modafinil (300 mg/kg) or caffeine (75 mg/kg), at doses that are strongly alerting. Spatial analysis revealed few regional differences in the percentage of cells double-labelled for hypocretin-1 and c-FOS following each treatment. These results suggest that activation of hypocretin neurons (as in the restraint condition) is not sufficient to induce phase shifts, and that gating of arousal effects on circadian clock phase may be downstream from the hypocretin system and from IGL neurons activated by these procedures.
Asunto(s)
Nivel de Alerta/fisiología , Ritmo Circadiano/fisiología , Hipotálamo/fisiología , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Neuronas/metabolismo , Neuropéptidos/metabolismo , Tálamo/fisiología , Animales , Compuestos de Bencidrilo/farmacología , Estimulantes del Sistema Nervioso Central/farmacología , Cricetinae , Hipotálamo/efectos de los fármacos , Inmunohistoquímica , Péptidos y Proteínas de Señalización Intracelular/efectos de los fármacos , Mesocricetus , Modafinilo , Neuronas/efectos de los fármacos , Neuropéptidos/efectos de los fármacos , Orexinas , Estimulación Física , Proteínas Proto-Oncogénicas c-fos/efectos de los fármacos , Proteínas Proto-Oncogénicas c-fos/metabolismo , Estrés Psicológico , Tálamo/efectos de los fármacosRESUMEN
It has been suggested that while the sialogogue pilocarpine elicits salivary secretion by acting directly on acinar cells of the salivary glands, it induces drinking behavior by acting on muscarinic receptors in the central nervous system. To study which brain regions are affected by the peripherally injected pilocarpine, we investigated changes in the numbers of c-Fos immunoreactive cells. The injections increased the numbers of c-Fos immunoreactive cells in the subfornical organ, median nucleus of preoptic area, organum vasculosum of lamina terminalis, paraventricular nucleus and supraoptic nucleus. Intracerebroventricular injection of pilocarpine produced similar changes in the expression of c-Fos immunoreactivity. The increases in immunoreactive expression induced by both the intraperitoneally and intracerebroventricularly injected pilocarpine were suppressed by previous intracerebroventricular injection of the muscarinic receptor antagonist atropine. Electrophysiological experiments using slice preparations and whole cell recordings showed that pilocarpine depolarized the membrane of neurons in the subfornical organ and suppressed the inhibitory GABAergic synaptic currents by a presynaptic action. The results suggest that peripherally applied pilocarpine does not act only on the salivary glands as a sialogogue, but also evokes thirst sensation by acting on the center controlling body fluid balance in the central nervous system.
Asunto(s)
Hipotálamo/fisiología , Salivación/fisiología , Órgano Subfornical/fisiología , Sed/fisiología , Equilibrio Hidroelectrolítico/fisiología , Animales , Biomarcadores/análisis , Biomarcadores/metabolismo , Mapeo Encefálico , Hipotálamo/efectos de los fármacos , Inmunohistoquímica , Inyecciones Intraperitoneales , Masculino , Agonistas Muscarínicos/farmacología , Antagonistas Muscarínicos/farmacología , Inhibición Neural/efectos de los fármacos , Inhibición Neural/fisiología , Técnicas de Cultivo de Órganos , Técnicas de Placa-Clamp , Pilocarpina/farmacología , Proteínas Proto-Oncogénicas c-fos/efectos de los fármacos , Proteínas Proto-Oncogénicas c-fos/metabolismo , Ratas , Ratas Wistar , Salivación/efectos de los fármacos , Órgano Subfornical/efectos de los fármacos , Transmisión Sináptica/efectos de los fármacos , Transmisión Sináptica/fisiología , Sed/efectos de los fármacos , Regulación hacia Arriba/fisiología , Equilibrio Hidroelectrolítico/efectos de los fármacos , Ácido gamma-Aminobutírico/metabolismoRESUMEN
AIM: To investigate the relationships between c-fos expression and oxidative stress or inflammation in the liver induced by acute cadmium (Cd) exposure. METHODS: Sixty male Sprague-Dawley rats were randomly assigned to 1 of 6 groups, 10 rats in each group. They were intragastrically pretreated with distilled water, distilled water, vitamin E (50 mg/100 g body weight), 25, 50 and 75% Sagittaria sagittifolia (SS) extract (2 ml/100 g weight) once a day for 10 consecutive days. Twenty-four hours after the last feeding, all animals were intraperitoneally administered CdCl(2) (20 micromol/kg body weight) except for the control group which was given distilled water. Twenty-four hours after intoxication, the glutathione (GSH) and malondialdehyde (MDA) contents and gene expression of tumor necrosis factor-alpha (TNF-alpha) and c-fos were measured in the livers. RESULTS: Acute Cd exposure significantly increased MDA levels, decreased GSH levels and upregulated the gene expression of TNF-alpha and c-fos in the liver. Vitamin E and middle and high doses of SS were able to inhibit the MDA level, but only middle and high doses of SS enhanced the GSH level and inhibited the upregulation of TNF-alpha gene expression. However, neither vitamin E nor SSwas able to inhibit the upregulation of c-fos gene expression in the liver. CONCLUSION: Our data suggested that c-fos induction is independent of oxidative stress or inflammation in the liver during the process of acute Cd exposure in rats.