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Métodos Terapéuticos y Terapias MTCI
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1.
BMC Neurosci ; 20(1): 33, 2019 07 10.
Artículo en Inglés | MEDLINE | ID: mdl-31291887

RESUMEN

BACKGROUND: Hypothalamic inflammation including astrogliosis and microglia activation occurs after intake of high fat diet (HFD) in rodent models or in obese individuals. However, the effect of chronic HFD feeding on oligodendrocytes (OLGs), a myelin-producing glial population in the central nervous system (CNS), remains unclear. In this study, we used 8-week old male C57BL/6 mice fed by HFD for 3-6 months to induce chronic obesity. RESULTS: The transmission electron microscopy imaging analysis showed that the integrity of hypothalamic myelin was disrupted after HFD feeding for 4 and 6 months. Moreover, the accumulation of Iba1+-microglia with an amoeboid hypertrophic form was continually observed in arcuate nucleus of HFD-fed mice during the entire feeding time period. Interleukin-33 (IL-33), a tissue alarmin upon injury to the CNS, was detected with an increased level in hypothalamus after HFD feeding for 3 and 4 months. Furthermore, the in vitro study indicated that exposure of mature OLGs to IL-33 impaired OLG cell structure along with a decline in the expression of myelin basic protein. CONCLUSIONS: Altogether, our findings demonstrate that chronic HFD feeding triggers hypothalamic myelin disruption in accompany with IL-33 upregulation and prolonged microglial activation in hypothalamus. Given that the addition of exogenous IL-33 was harmful for the maturation of OLGs, an increase in IL-33 by chronic HFD feeding might contribute to the induction of hypothalamic myelin disruption.


Asunto(s)
Dieta Alta en Grasa/efectos adversos , Hipotálamo/metabolismo , Interleucina-33/metabolismo , Vaina de Mielina/patología , Regulación hacia Arriba , Animales , Núcleo Arqueado del Hipotálamo/metabolismo , Núcleo Arqueado del Hipotálamo/patología , Hipotálamo/patología , Masculino , Ratones , Proteína Básica de Mielina/biosíntesis , Vaina de Mielina/metabolismo , Oligodendroglía/metabolismo , Oligodendroglía/patología , Cultivo Primario de Células , Ratas , Factores de Tiempo
2.
J Neurosci Res ; 91(5): 694-705, 2013 May.
Artículo en Inglés | MEDLINE | ID: mdl-23404572

RESUMEN

Peripheral injection with a high dose of valproic acid (VPA), a histone deacetylase (HDAC) inhibitor, into animals with mild or moderate spinal cord injury (SCI) for 1 week can reduce spinal cord tissue loss and promote hindlimb locomotor recovery. A purinergic adenosine triphosphate (ATP) receptor subtype, P2X4 receptor (P2X4 R), has been considered as a potential target to diminish SCI-associated inflammatory responses. In this study, using a minipump-based infusion system, we found that intraspinal infusion with VPA for 3 days into injured spinal cord significantly improved hindlimb locomotion of rats with severe SCI induced by a 10-g NYU impactor dropping from the height of 50 mm onto the spinal T9/10 segment. The neuronal fibers in the injured spinal cord tissues were significantly preserved in VPA-treated rats compared with those observed in vehicle-treated animals. Moreover, the accumulation of microglia/macrophages and astrocytes in the injured spinal cord was attenuated in the animal group receiving VPA infusion. VPA also significantly reduced P2X4 R expression post-SCI. Furthermore, in vitro study indicated that VPA, but not the other HDAC inhibitors, sodium butyrate and trichostatin A (TSA), caused downregulation of P2X4 R in microglia activated with lipopolysaccharide (LPS). Moreover, p38 mitogen-activated protein kinase (MAPK)-triggered signaling was involved in the effect of VPA on the inhibition of P2X4 R gene expression. In addition to the findings from others, our results also provide important evidence to show the inhibitory effect of VPA on P2X4 R expression in activated microglia, which may contribute to reduction of SCI-induced gliosis and subsequently preservation of spinal cord tissues. © 2013 Wiley Periodicals, Inc.


Asunto(s)
Inhibidores Enzimáticos/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Microglía/efectos de los fármacos , Receptores Purinérgicos P2X4/metabolismo , Traumatismos de la Médula Espinal/patología , Ácido Valproico/farmacología , Animales , Catalasa/metabolismo , Células Cultivadas , Modelos Animales de Enfermedad , Inhibidores Enzimáticos/uso terapéutico , Femenino , Proteína Ácida Fibrilar de la Glía/metabolismo , Miembro Posterior/fisiopatología , Locomoción/efectos de los fármacos , Macrófagos/efectos de los fármacos , Macrófagos/patología , Fibras Nerviosas/metabolismo , Proteínas de Neurofilamentos/metabolismo , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores Purinérgicos P2X4/genética , Traumatismos de la Médula Espinal/tratamiento farmacológico , Superóxido Dismutasa/metabolismo , Ácido Valproico/uso terapéutico
3.
J Neurochem ; 121(4): 537-50, 2012 May.
Artículo en Inglés | MEDLINE | ID: mdl-22380620

RESUMEN

Astrocytic glutamate transporter-1 (GLT-1) is responsible for 90% of forebrain glutamate uptake in the adult CNS. Retinoic acid (RA) is a potent regulator of neural cell differentiation and neuronal maturation in the developing CNS through activation of RA receptors/retinoic X receptors (RXRs) or non-genomic mechanisms. Although rat GLT-1 contains several RXR binding regions, RA-triggered RXR mechanisms regulating GLT-1 expression remain unknown. RA applied at submicromolar concentrations for 24 h significantly reduced GLT-1 mRNA and membrane levels in astrocytes and dibutyryl cAMP (dbcAMP)-primed astrocytes. An RXR agonist reduced astrocytic GLT-1 mRNA expression, whereas an RXR antagonist blocked the effects of RA on the reduction of astrocytic GLT-1 mRNA expression. Electrophoresis motility shift assay indicated that RA-treatment increased astrocytic RXR-DNA binding activity. RA-induced reduction in GLT-1 mRNA expression was also observed in dbcAMP-primed astrocytes. Through lentivirus-mediated astrocytic over-expression of rat GLT-1, levels of GLT-1 in the processes of dbcAMP-treated astrocytes were attenuated by exposure to RA. The protein kinase C inhibitor, Bis I, restored GLT-1 distribution in the processes of RA-treated dbcAMP-primed astrocytes. These results suggest that RA reduces astrocytic GLT-1 levels through both RXR-mediated inhibition at the transcriptional level and triggering activation of protein kinase C which reduces cell surface GLT-1 levels.


Asunto(s)
Astrocitos/metabolismo , Transportador 1 de Aminoácidos Excitadores/biosíntesis , Proteína Quinasa C/fisiología , Receptores X Retinoide/efectos de los fármacos , Tretinoina/farmacología , Actinas/metabolismo , Animales , Astrocitos/efectos de los fármacos , Bucladesina/farmacología , ADN Complementario/biosíntesis , ADN Complementario/genética , Regulación hacia Abajo/efectos de los fármacos , Ensayo de Cambio de Movilidad Electroforética , Transportador 1 de Aminoácidos Excitadores/genética , Ácido Glutámico/metabolismo , Heterocigoto , Lentivirus/genética , Neuroglía/metabolismo , Neuronas/metabolismo , ARN Mensajero/biosíntesis , ARN Mensajero/genética , Ratas , Ratas Sprague-Dawley , Reacción en Cadena en Tiempo Real de la Polimerasa , Receptores de Superficie Celular/metabolismo , Receptores X Retinoide/genética , Transducción de Señal/efectos de los fármacos
4.
Br J Pharmacol ; 158(3): 713-25, 2009 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-19663884

RESUMEN

BACKGROUND AND PURPOSE: Natural compounds obtained from marine organisms have received considerable attention as potential sources of novel drugs for treatment of human inflammatory diseases. Capnellene, isolated from the marine soft coral Capnella imbricate, 4,4,6a-trimethyl-3-methylene-decahydro-cyclopenta[]pentalene-2,3a-diol (GB9) exhibited anti-inflammatory actions on activated macrophages in vitro. Here we have assessed the anti-neuroinflammatory properties of GB9 and its acetylated derivative, acetic acid 3a-hydroxy-4,4,6a-trimethyl-3-methylene-decahydro-cyclopenta[]pentalen-2-yl ester (GB10). EXPERIMENTAL APPROACH: Effects of GB9 or GB10 on the expression of inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2) in interferon-gamma (IFN-gamma)-stimulated mouse microglial BV2 cells were measured by Western blot. The in vivo effects of these compounds were examined in the chronic constriction injury (CCI) rat model of neuropathic pain, measuring thermal hyperalgesia, and microglial activation and COX-2 protein in lumbar spinal cord, by immunohistochemistry. KEY RESULTS: In BV2 cells, GB9 and GB10 inhibited the expression of iNOS and COX-2, stimulated by IFN-gamma. Intrathecal administration of GB9 and GB10 inhibited CCI-induced nociceptive sensitization and thermal hyperalgesia in a dose-dependent manner. Intraperitoneal injection of GB9 inhibited CCI-induced thermal hyperalgesia and also inhibited CCI-induced activation of microglial cells and up-regulation of COX-2 in the dorsal horn of the lumbar spinal cord ipsilateral to the injury. CONCLUSION AND IMPLICATIONS: Taken together, these data indicate that the marine-derived capnellenes, GB9 and GB10, had anti-neuroinflammatory and anti-nociceptive properties in IFN-gamma-stimulated microglial cells and in neuropathic rats respectively. Therefore, capnellene may serve as a useful lead compound in the search for new therapeutic agents for treatment of neuroinflammatory diseases.


Asunto(s)
Analgésicos/uso terapéutico , Antozoos/química , Antiinflamatorios no Esteroideos/uso terapéutico , Dolor/tratamiento farmacológico , Enfermedades del Sistema Nervioso Periférico/tratamiento farmacológico , Sesquiterpenos/uso terapéutico , Analgésicos/farmacología , Animales , Antiinflamatorios no Esteroideos/farmacología , Línea Celular , Constricción Patológica/complicaciones , Ciclooxigenasa 2/biosíntesis , Inhibidores de la Ciclooxigenasa 2/farmacología , Inhibidores de la Ciclooxigenasa 2/uso terapéutico , Hiperalgesia/tratamiento farmacológico , Interferón gamma/farmacología , Región Lumbosacra , Masculino , Ratones , Microglía/efectos de los fármacos , Microglía/enzimología , Neuronas/efectos de los fármacos , Neuronas/enzimología , Óxido Nítrico Sintasa de Tipo II/antagonistas & inhibidores , Óxido Nítrico Sintasa de Tipo II/biosíntesis , Dolor/etiología , Dolor/fisiopatología , Enfermedades del Sistema Nervioso Periférico/etiología , Enfermedades del Sistema Nervioso Periférico/fisiopatología , Ratas , Ratas Wistar , Sesquiterpenos/farmacología , Médula Espinal/efectos de los fármacos , Médula Espinal/enzimología , Regulación hacia Arriba
5.
J Cell Biochem ; 103(3): 825-34, 2008 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-17631669

RESUMEN

Exposure of the brain to cadmium ions (Cd(2+)) is believed to lead to neurological disorders of the central nervous system (CNS). In this study, we tested the hypothesis that astrocytes, the major CNS-supporting cells, are resistant to Cd(2+)-induced injury compared with cortical neurons and microglia (CNS macrophages). However, treatment with CdCl(2) for 24 h at concentrations higher than 20 microM substantially induced astrocytic cytotoxicity, which also resulted from long-term exposure to 5 microM of CdCl(2). Intracellular calcium levels were found to rapidly increase after the addition of CdCl(2) into astrocytes, which led to a rise in reactive oxygen species (ROS) and to mitochondrial impairment. In accordance, preexposure to the extracellular calcium chelator EGTA effectively reduced ROS production and increased survival of Cd(2+)-treated astrocytes. Adenovirus-mediated transfer of superoxide dismutase (SOD) or glutathione peroxidase (GPx) genes increased survival of Cd(2+)-exposed astrocytes. In addition, increased ROS generation and astrocytic cell death due to Cd(2+) exposure was inhibited when astrocytes were treated with the polyphenolic compound ellagic acid (EA). Taken together, Cd(2+)-induced astrocytic cell death resulted from disrupted calcium homeostasis and an increase in ROS. Moreover, our findings demonstrate that enhancement of the activity of intracellular antioxidant enzymes and supplementation with a phenolic compound, a natural antioxidant, improves survival of Cd(2+)-primed astrocytes. This information provides a useful approach for treating Cd(2+)-induced CNS neurological disorders.


Asunto(s)
Antioxidantes/farmacología , Astrocitos/metabolismo , Cloruro de Cadmio/toxicidad , Calcio/metabolismo , Glutatión Reductasa/farmacología , Especies Reactivas de Oxígeno/farmacología , Superóxido Dismutasa/farmacología , Animales , Animales Recién Nacidos , Antioxidantes/uso terapéutico , Apoptosis/efectos de los fármacos , Astrocitos/efectos de los fármacos , Cloruro de Cadmio/química , Calcio/química , Calcio/farmacología , Células Cultivadas , Relación Dosis-Respuesta a Droga , Ácido Egtácico/química , Ácido Egtácico/farmacología , Glutatión Reductasa/metabolismo , Oxidación-Reducción , Ratas , Ratas Sprague-Dawley , Especies Reactivas de Oxígeno/metabolismo , Superóxido Dismutasa/metabolismo
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