RESUMEN
BACKGROUND AND PURPOSE: Multiple sclerosis (MS) patients discontinuing natalizumab are at risk of rebound of disease activity. METHODS: In the present multi-center, open-label, non-randomized, prospective, pilot study, we tested whether treatment with glatiramer acetate (GA) is safe and effective after natalizumab in MS patients. The study was performed at academic tertiary medical centers. Forty active relapsing-remitting MS patients who never failed GA therapy and who discontinued natalizumab after 12-18 months of therapy were enrolled. GA was initiated 4 weeks after the last dose of natalizumab. RESULTS: 62.5% of patients were relapse-free 12 months after GA initiation. Annualized relapse rate and time to relapse were significantly lower than before natalizumab. Notably, the frequency of relapses was significantly lower amongst those patients who had experienced ≤2 relapses the year before initiation of natalizumab therapy, compared with patients who had had three or more relapses. No evidence of rebound was observed in magnetic resonance imaging scans. Furthermore, Expanded Disability Status Scale and Multiple Sclerosis Functional Composite were stable in our patients, again suggesting that 12 months of post-natalizumab-GA therapy is not associated with clinical deterioration. CONCLUSIONS: Following discontinuation of natalizumab, 12 months of therapy with GA is safe and well tolerated in MS patients. GA can reduce the risk of early reactivation/rebound of disease activity in this setting.
Asunto(s)
Inmunosupresores/uso terapéutico , Esclerosis Múltiple/tratamiento farmacológico , Péptidos/uso terapéutico , Adolescente , Adulto , Anticuerpos Monoclonales Humanizados/uso terapéutico , Corteza Cerebral/patología , Evaluación de la Discapacidad , Progresión de la Enfermedad , Femenino , Acetato de Glatiramer , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Natalizumab , Evaluación de Resultado en la Atención de Salud , Proyectos Piloto , Estudios Prospectivos , Recurrencia , Médula Espinal/patología , Estadísticas no Paramétricas , Factores de Tiempo , Adulto JovenRESUMEN
BACKGROUND: Inflammation triggers secondary neurodegeneration in multiple sclerosis (MS). OBJECTIVES: It is unclear whether classical anti-inflammatory cytokines have the potential to interfere with synaptic transmission and neuronal survival in MS. METHODS: Correlation analyses between cerebrospinal fluid (CSF) contents of anti-inflammatory cytokines and molecular, imaging, clinical, and neurophysiological measures of neuronal alterations were performed. RESULTS: Our data suggest that interleukin-13 (IL-13) plays a neuroprotective role in MS brains. We found, in fact, that the levels of IL-13 in the CSF of MS patients were correlated with the contents of amyloid-ß(1-42). Correlations were also found between IL-13 and imaging indexes of axonal and neuronal integrity, such as the retinal nerve fibre layer thickness and the macular volume evaluated by optical coherence tomography. Furthermore, the levels of IL-13 were related to better performance in the low-contrast acuity test and Multiple Sclerosis Functional Composite scoring. Finally, by means of transcranial magnetic stimulation, we have shown that GABAA-mediated cortical inhibition was more pronounced in patients with high IL-13 levels in the CSF, as expected for a neuroprotective, anti-excitotoxic effect. CONCLUSIONS: The present correlation study provides some evidence for the involvement of IL-13 in the modulation of neuronal integrity and synaptic function in patients with MS.
Asunto(s)
Interleucina-13/líquido cefalorraquídeo , Corteza Motora/inmunología , Esclerosis Múltiple Recurrente-Remitente/inmunología , Degeneración Nerviosa/inmunología , Neuronas/inmunología , Adulto , Péptidos beta-Amiloides/líquido cefalorraquídeo , Biomarcadores/líquido cefalorraquídeo , Estudios de Casos y Controles , Distribución de Chi-Cuadrado , Sensibilidad de Contraste , Evaluación de la Discapacidad , Potenciales Evocados Motores , Femenino , Humanos , Italia , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Corteza Motora/patología , Corteza Motora/fisiopatología , Esclerosis Múltiple Recurrente-Remitente/líquido cefalorraquídeo , Esclerosis Múltiple Recurrente-Remitente/diagnóstico , Esclerosis Múltiple Recurrente-Remitente/patología , Esclerosis Múltiple Recurrente-Remitente/fisiopatología , Degeneración Nerviosa/líquido cefalorraquídeo , Degeneración Nerviosa/patología , Degeneración Nerviosa/fisiopatología , Degeneración Nerviosa/prevención & control , Neuronas/patología , Fragmentos de Péptidos/líquido cefalorraquídeo , Transmisión Sináptica , Tomografía de Coherencia Óptica , Estimulación Magnética Transcraneal , Adulto JovenRESUMEN
Hemiballism (HB) is a quite rare disorder, generally secondary to stroke, neoplasms or demyelinating plaques, classically considered as almost pathognomonic of a lesion in the subthalamic nucleus (STN). This alteration causes involuntary movements in the chorea-ballism spectrum. One theory is that the output nuclei of the basal ganglia are overinhibited in HB, while little is known about the physiological state of the striatum, the major input structure of the basal ganglia. In the present study, we recorded spontaneous and miniature excitatory and inhibitory postsynaptic currents (sEPSCs, mEPSCs, sIPSCs, mIPSCs) from projection neurons of the striatum of experimental HB. We found a selective reduction of striatal sEPSC and mEPSC frequency following chemical lesion of the STN of the rat, suggesting that reduced synaptic excitation of the input structure of the basal ganglia represents a physiological correlate of HB.
Asunto(s)
Cuerpo Estriado/fisiopatología , Discinesias/patología , Ácido Glutámico/metabolismo , Transmisión Sináptica/fisiología , Anestésicos Locales/farmacología , Animales , Modelos Animales de Enfermedad , Antagonistas de Dopamina/farmacología , Discinesias/fisiopatología , Estimulación Eléctrica/métodos , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Potenciales Postsinápticos Excitadores/fisiología , Potenciales Postsinápticos Excitadores/efectos de la radiación , Técnicas In Vitro , Potenciales Postsinápticos Inhibidores/efectos de los fármacos , Potenciales Postsinápticos Inhibidores/fisiología , Potenciales Postsinápticos Inhibidores/efectos de la radiación , Técnicas de Placa-Clamp/métodos , Ratas , Ratas Sprague-Dawley , Sulpirida/farmacología , Transmisión Sináptica/efectos de los fármacos , Transmisión Sináptica/efectos de la radiación , Tetrodotoxina/farmacología , Triazinas/farmacología , Triazoles/farmacologíaRESUMEN
Proinflammatory cytokines such as tumor necrosis factor-α and interleukin-1ß (IL1ß) regulate both excitatory and inhibitory synaptic transmission in the central nervous system. The interaction between IL1ß and endocannabinoid system (ECS) is also emerging, based on the evidence that IL1ß effects on striatal spontaneous excitatory and inhibitory postsynaptic currents are regulated by transient receptor potential vanilloid 1 (TRPV1) channels, members of the ECS. Furthermore, IL1ß has also been shown to control the sensitivity of cannabinoid CB1 receptors controlling GABA transmission (CB1Rs(GABA)) in the striatum. To better detail the synaptic action of IL1ß, and to clarify its complex interaction with the ECS, here we investigated the possible interplay between IL1ß and CB1Rs controlling glutamate transmission (CB1Rs(glu)), other critical elements of the ECS. Our results show that the sensitivity of CB1Rs(glu) is fully blocked in the presence of IL1ß in corticostriatal brain slices, and that the protein kinase C/TRPV1 pathway is involved in this effect. IL1ß failed to modulate the sensitivity of glutamate synapses to the stimulation of GABAB receptors. We also provided evidence that IL1ß-CB1Rs(GABA) but not IL1ß-CB1Rs(glu) interaction is under the control of the brain-derived neurotrophic factor (BDNF)/trkB signaling and of lipid raft composition, because BDNF gene partial deletion, pharmacological blockade of trkB and membrane cholesterol removal with methyl-ß-cyclodextrin all blocked IL1ß-mediated inhibition of CB1Rs(GABA) but left unaltered the sensitivity of CB1Rs(glu) to this cytokine. Our results provide further evidence that synaptic transmission and the ECS are regulated by IL1ß in the striatum.
Asunto(s)
Ácido Glutámico/fisiología , Interleucina-1beta/farmacología , Neostriado/efectos de los fármacos , Receptor Cannabinoide CB1/efectos de los fármacos , Transmisión Sináptica/efectos de los fármacos , Animales , Factor Neurotrófico Derivado del Encéfalo/farmacología , Dronabinol/análogos & derivados , Dronabinol/farmacología , Fenómenos Electrofisiológicos , Antagonistas de Aminoácidos Excitadores/farmacología , Masculino , Microdominios de Membrana/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Neostriado/metabolismo , Proteína Quinasa C/genética , Proteína Quinasa C/fisiología , Receptores de GABA-B/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Sinapsis/efectos de los fármacos , Canales Catiónicos TRPV/genética , Canales Catiónicos TRPV/fisiologíaRESUMEN
BACKGROUND AND PURPOSE: Glutamate transmission is dysregulated in both multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE), the animal model of MS. A characteristic of EAE is increased glutamate transmission associated with up-regulation of AMPA receptors. However, little is known about the role of NMDA receptors in the synaptic modifications induced by EAE. EXPERIMENTAL APPROACH: The contribution of NMDA receptors to the alterations of glutamate transmission and disease severity in EAE mice was assessed by means of neurophysiological, morphological, Western blot, metabolic and clinical score assessments. KEY RESULTS: In our EAE mice, there was an NMDA receptor-dependent increase of glutamate release, associated with marked activation of the astroglia. Presynaptic NMDA receptors became overactive during EAE, increasing synaptic glutamate release by a mechanism dependent on voltage-gated sodium channels. By means of NAD(P)H autofluorescence analysis, we also found that EAE has a glutamate and NMDA receptor-dependent dysfunction of mitochondrial activity, which is known to contribute to the neurodegenerative damage of MS and EAE. Furthermore, pharmacological blockade of NMDA receptors in vivo ameliorated both synaptic transmission defects and of the clinical disease course of EAE mice, while EAE induced in mice with a genetically enhanced NMDA receptor signalling had opposite effects. CONCLUSIONS AND IMPLICATIONS: Our data, showing both sensitization of NMDA receptors and their involvement in the progression of the EAE disease, supggest that pharmacological impairment of NMDA receptor signalling would be a component of a neuroprotection strategy in MS.
Asunto(s)
Encefalomielitis Autoinmune Experimental/fisiopatología , Ácido Glutámico/fisiología , Receptores de N-Metil-D-Aspartato/fisiología , Animales , Maleato de Dizocilpina/farmacología , Encefalomielitis Autoinmune Experimental/metabolismo , Antagonistas de Aminoácidos Excitadores/farmacología , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Femenino , Ratones , Ratones Endogámicos C57BL , Ratones Mutantes , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Sinapsis/fisiología , Canales de Sodio Activados por Voltaje/fisiologíaRESUMEN
BACKGROUND AND PURPOSE Alterations of glutamate-mediated synaptic transmission occur early during neuroinflammatory insults, and lead to degenerative neuronal damage in multiple sclerosis (MS) and also in experimental autoimmune encephalomyelitis (EAE), which is a murine model of MS. Fingolimod is an effective orally active agent for the treatment of MS, affecting lymphocyte invasion of the brain. However, it is still unclear if fingolimod can be neuroprotective in this disorder. EXPERIMENTAL APPROACH Using neurophysiological recordings and morphological evaluation of dendritic integrity, we evaluated the effects of oral fingolimod on the clinical score of EAE mice in order to determine whether the compound was associated with preservation of synaptic transmission. KEY RESULTS Oral fingolimod prevented and reversed the pre- and postsynaptic alterations of glutamate transmission in EAE mice. These effects were associated with a clear amelioration of the clinical deterioration seen in EAE mice, and with a significant inhibition of neuronal dendritic pathology. Fingolimod did not alter the spontaneous excitatory postsynaptic currents in control animals, suggesting that only the pathological processes behind the inflammation-induced defects in glutamate transmission were modulated by this compound. CONCLUSIONS AND IMPLICATIONS The beneficial effects of fingolimod on the clinical, synaptic and dendritic abnormalities of murine EAE might correlate with the neuroprotective actions of this agent, as observed in MS patients. LINKED ARTICLE This article is commented on by Gillingwater, pp. 858-860 of this issue. To view this commentary visit http://dx.doi.org/10.1111/j.1476-5381.2011.01612.x.
Asunto(s)
Encefalomielitis Autoinmune Experimental/fisiopatología , Inmunosupresores/farmacología , Esclerosis Múltiple/fisiopatología , Glicoles de Propileno/farmacología , Esfingosina/análogos & derivados , Sinapsis/efectos de los fármacos , Animales , Espinas Dendríticas/efectos de los fármacos , Espinas Dendríticas/patología , Encefalomielitis Autoinmune Experimental/inducido químicamente , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Encefalomielitis Autoinmune Experimental/patología , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Femenino , Clorhidrato de Fingolimod , Ácido Glutámico/fisiología , Glicoproteínas , Inmunosupresores/uso terapéutico , Ratones , Ratones Endogámicos C57BL , Esclerosis Múltiple/tratamiento farmacológico , Esclerosis Múltiple/patología , Glicoproteína Mielina-Oligodendrócito , Fragmentos de Péptidos , Glicoles de Propileno/uso terapéutico , Esfingosina/farmacología , Esfingosina/uso terapéutico , Sinapsis/fisiología , Transmisión Sináptica/efectos de los fármacosRESUMEN
The neurotransmitter acetylcholine (Ach) controls both excitatory and inhibitory synaptic transmission in the striatum. Here, we investigated the involvement of the endocannabinoid system in Ach-mediated inhibition of striatal GABA transmission, and the potential role of transient receptor potential vanilloid 1 (TRPV1) channels in the control of Ach-endocannabinoid coupling. We found that inhibition of Ach degradation and direct pharmacological stimulation of muscarinic M1 receptors reduced striatal inhibitory postsynaptic currents (IPSCs) through the stimulation of 2-arachidonoylglicerol (2AG) synthesis and the activation of cannabinoid CB1 receptors. The effects of M1 receptor activation on IPSCs were occlusive with those of metabotropic glutamate receptor 5 stimulation, and were prevented in the presence of capsaicin, agonist of TRPV1 channels. Elevation of anandamide (AEA) tone with URB597, a blocker of fatty acid amide hydrolase, mimicked the effects of capsaicin, indicating that endogenous AEA acts as an endovanilloid substance in the control of M1-dependent 2AG-mediated synaptic effects in the striatum. Accordingly, both capsaicin and URB597 effects were absent in mice lacking TRPV1 channels. Pharmacological interventions targeting AEA metabolism and TRPV1 channels might be considered alternative therapeutic routes in disorders of striatal cholinergic or endocannabinoid neurotransmission.