Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 10 de 10
Filtrar
Más filtros










Base de datos
Intervalo de año de publicación
1.
Pathol Biol (Paris) ; 57(2): 117-26, 2009 Mar.
Artículo en Francés | MEDLINE | ID: mdl-18848406

RESUMEN

Transmissible spongiform encephalopathies (TSEs), are fatal neurodegenerative diseases caused by unconventional agents, the prions. They are characterised by the accumulation in infected tissues of an abnormally folded form of the host-encoded prion protein (PrP). This pathological form is partially resistant to protease digestion, leading to the production of so-called PrP(res) fragments. Different isolates from the same host species may show different eletrophoretic profiles, reflecting the existence of different prion strains. The active surveillance of ruminant TSEs implemented in European countries, based on a large-scale biochemical testing of brain tissue samples from carcasses, has revealed PrP(res) profiles unnoticed so far. Experimental transmission of these atypical cases to various transgenic mouse lines has led to the recognition of a novel scrapie strain in sheep and goats, called Nor98, and of two variant strains of spongiform encephalopathy in cattle. This review is aimed at summarising the current knowledge on these newly recognised forms of ruminants TSEs, and at discussing their possible origin and potential implications in terms of animal and human health.


Asunto(s)
Enfermedades por Prión/transmisión , Enfermedades por Prión/veterinaria , Rumiantes , Animales , Ratones , Ratones Transgénicos , Polimorfismo Genético , Priones/genética , Priones/aislamiento & purificación , Scrapie/diagnóstico , Scrapie/transmisión , Ovinos , Enfermedades de las Ovejas/diagnóstico
2.
J Virol ; 74(12): 5432-40, 2000 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-10823847

RESUMEN

The mode and the site of action of the major antiscrapie drugs have been studied by investigating their effects on the abnormal protease-resistant isoform of PrP (PrPres) and on its accumulation in mouse spleen. Day-by-day PrPres accumulation in the spleen and in other peripheral organs was first monitored to describe the early steps of scrapie pathogenesis. Three phases were identified: the detection of scrapie inoculum on the day of scrapie infection, a clearance phase, and then the peripheral accumulation of PrPres. In a second step, the effects of the polyene antibiotic MS-8209, the polyanion dextran sulfate 500 (DS500), and Congo red were assessed on these phases, after the drugs were coincubated with scrapie inoculum. Highly different mechanisms and sites of action were apparent. MS-8209 had a weak effect on the accumulation of PrPres in spleen, suggesting another site of intervention for this drug. DS500 delayed the beginning of the clearance phase but then blocked PrPres synthesis for a long period of time, probably because of its immunological effects on the spleen. Surprisingly, Congo red suppressed the clearance phase of scrapie inoculum and then increased transiently accumulation of PrPres in spleen. We showed in vitro that this effect was related to a direct enhancement of the protease resistance of PrPres by the drug.


Asunto(s)
Anfotericina B/análogos & derivados , Rojo Congo/farmacología , Sulfato de Dextran/farmacología , Proteínas PrPSc/metabolismo , Scrapie/metabolismo , Bazo/efectos de los fármacos , Anfotericina B/administración & dosificación , Anfotericina B/metabolismo , Anfotericina B/farmacología , Anfotericina B/uso terapéutico , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/patología , Rojo Congo/administración & dosificación , Rojo Congo/metabolismo , Rojo Congo/uso terapéutico , Cricetinae , Sulfato de Dextran/administración & dosificación , Sulfato de Dextran/metabolismo , Sulfato de Dextran/uso terapéutico , Relación Dosis-Respuesta a Droga , Endopeptidasa K/metabolismo , Femenino , Inyecciones Intraperitoneales , Cinética , Ratones , Ratones Endogámicos C57BL , Ratones SCID , Especificidad de Órganos , Proteínas PrPSc/administración & dosificación , Proteínas PrPSc/antagonistas & inhibidores , Proteínas PrPSc/aislamiento & purificación , Unión Proteica , Isoformas de Proteínas/administración & dosificación , Isoformas de Proteínas/antagonistas & inhibidores , Isoformas de Proteínas/aislamiento & purificación , Isoformas de Proteínas/metabolismo , Scrapie/tratamiento farmacológico , Scrapie/patología , Bazo/química , Bazo/metabolismo , Bazo/patología , Factores de Tiempo
3.
J Pathol ; 190(4): 495-502, 2000 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-10700001

RESUMEN

The involvement of spleen macrophages in the early stages of scrapie pathogenesis was studied by applying the 'macrophage-suicide technique' to scrapie-infected mice. This method comprises critically the intravenous administration to mice of dichloromethylene disphosphonate encapsulated into liposomes. Depletion of spleen macrophages before scrapie infection induced an increased amount of scrapie inoculum in the spleen, consequently leading to accelerated scrapie agent replication in the early phase of pathogenesis, as followed by PrPres accumulation, a specific hallmark of scrapie. The same effect was observed when spleen macrophages were depleted just before the beginning of scrapie agent replication. These findings suggest that macrophages may partly control scrapie infection in peripheral tissues by sequestration of the scrapie inoculum and may thus impair early scrapie agent replication in the spleen. In addition to macrophages, most follicular dendritic cells and B lymphocytes, which are thought to support scrapie agent replication, were also transiently depleted by dichloromethylene disphosphonate administration. This suggests that a compensatory mechanism is sufficient to ensure the persistence of infection in these early stages of pathogenesis.


Asunto(s)
Macrófagos/inmunología , Scrapie/inmunología , Bazo/inmunología , Analgésicos no Narcóticos/farmacología , Animales , Linfocitos B/efectos de los fármacos , Linfocitos B/inmunología , Ácido Clodrónico/farmacología , Macrófagos/efectos de los fármacos , Ratones , Priones/metabolismo , Scrapie/virología , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología
4.
Antimicrob Agents Chemother ; 44(2): 405-7, 2000 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-10639370

RESUMEN

Amphotericin B derivatives, such as MS-8209, have been evaluated as a therapeutic approach to human immunodeficiency virus (HIV) infection. We show that MS-8209, like amphotericin B, increases tumor necrosis factor alpha (TNF-alpha) mRNA expression and TNF-alpha production and consequently HIV replication in human macrophages. These effects confirm the pharmacological risk associated with the administration of amphotericin B or its derivatives to HIV-infected patients.


Asunto(s)
Anfotericina B/análogos & derivados , Fármacos Anti-VIH/farmacología , VIH/efectos de los fármacos , Macrófagos/virología , Factor de Necrosis Tumoral alfa/biosíntesis , Anfotericina B/farmacología , VIH/fisiología , Humanos , Macrófagos/metabolismo , ARN Mensajero/biosíntesis , Factores de Riesgo , Factor de Necrosis Tumoral alfa/efectos de los fármacos , Replicación Viral/efectos de los fármacos
5.
Arch Virol Suppl ; (16): 39-56, 2000.
Artículo en Inglés | MEDLINE | ID: mdl-11214934

RESUMEN

In most experimental models of scrapie and in some naturally infected species, the lymphoreticular system and the spleen in particular play a major role in the pathogenesis of the disease. Previous studies demonstrated scrapie infectivity in peripheral organs from the day of infection up to the terminal stage. The discovery of the abnormal prion protein, PrPres, as a specific molecular hallmark of scrapie should permit enhanced study of scrapie pathogenesis and has some pharmacological applications. In this study, PrPres accumulation was followed day by day in peripheral organs. Four different phases were identified: the circulation of scrapie inoculum, a clearance phase, the peripheral accumulation of PrPres and a plateau phase. This kinetics was then pharmacologically modified (i) by applying the macrophage "suicide" technique to unveil the cellular types involved in scrapie pathogenesis and (ii) with anti-scrapie drugs such as polyene antibiotics, polyanions and Congo red to investigate their mode and site of action.


Asunto(s)
Anfotericina B/farmacología , Rojo Congo/farmacología , Polímeros/farmacología , Proteínas PrPSc/metabolismo , Scrapie/tratamiento farmacológico , Bazo/metabolismo , Anfotericina B/administración & dosificación , Anfotericina B/análogos & derivados , Animales , Ácido Clodrónico/administración & dosificación , Ácido Clodrónico/farmacología , Rojo Congo/administración & dosificación , Endopeptidasas/metabolismo , Liposomas , Macrófagos/inmunología , Macrófagos/fisiología , Ratones , Ratones Endogámicos C57BL , Ratones SCID , Polielectrolitos , Polímeros/administración & dosificación , Scrapie/metabolismo , Distribución Tisular
6.
J Gen Virol ; 80 ( Pt 7): 1873-1877, 1999 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-10423158

RESUMEN

The polyene antibiotic MS-8209 is currently one of the most effective drugs in the treatment of experimental scrapie. However, its mechanism of action and its site of intervention in the pathogenetical process of scrapie infection are largely unknown. It has been shown previously that the infection of immunodeficient SCID mice by the peripheral route provides a reliable model for direct scrapie neuroinvasion, bypassing the lymphoreticular system. Indeed, a proportion of SCID mice develop scrapie after a similar time to immunocompetent mice, despite their severe immune impairment. This model is now used to clarify the targets of MS-8209. In SCID mice, MS-8209 treatment protected against infection but did not prolong survival time. In SCID mice immunologically reconstituted prior to inoculation, the drug delayed the disease without an effect on the attack rate. These findings strongly suggest that MS-8209 acts by hampering the first step of the neuroinvasion process, i.e. the uptake of the infectious agent by peripheral nerve endings. The mechanism leading to the inhibition of agent propagation to nervous cells is discussed with regard to the properties of polyene antibiotics.


Asunto(s)
Anfotericina B/análogos & derivados , Antivirales/uso terapéutico , Priones/efectos de los fármacos , Scrapie/prevención & control , Anfotericina B/farmacología , Anfotericina B/uso terapéutico , Animales , Antivirales/farmacología , Ratones , Ratones SCID , Sistema Nervioso/virología
7.
J Gen Virol ; 80 ( Pt 4): 1079-1085, 1999 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-10211979

RESUMEN

Amphotericin B (AmB) has been shown to delay hamster scrapie. Infectivity studies have been performed previously using AmB in order to understand the relationship between the accumulation of an abnormal isoform (PrPres) of the prion protein and 263K scrapie agent replication in the brain. The first study reported that AmB had no effect upon agent replication, although it delayed the development of both clinical signs and PrPres accumulation. However, subsequent experiments using the same model showed a significant effect both on agent replication and PrPres accumulation early in infection. This fundamental discrepancy was assumed to be linked to differences in experimental protocols. In order to unravel the issue, a new experiment has been performed encompassing different protocols and using an AmB derivative, MS-8209, that can be used at higher doses because of its lower toxicity. The findings of this study exclude the suspected differences in the protocols as the reason for previous conflicting results, and suggest strongly that these discrepancies were due to a low dose of AmB causing a 'threshold effect'. Overall, this study indicates that, in this model, PrPres cannot be dissociated from infectivity by polyene antibiotics.


Asunto(s)
Anfotericina B/análogos & derivados , Antivirales/farmacología , Proteínas PrPSc/efectos de los fármacos , Anfotericina B/farmacología , Animales , Cricetinae , Relación Dosis-Respuesta a Droga , Femenino , Mesocricetus , Proteínas PrPSc/metabolismo
8.
J Virol ; 71(12): 9685-9, 1997 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-9371634

RESUMEN

Amphotericin B (AmB) is one of the few drugs able to prolong survival times in experimental scrapie and delays the accumulation of PrPres, a specific marker of this disease in the brain in vivo. Previous reports showed that the AmB effect is observed only if the drug is administered around the time of infection. In the present study, intracerebrally infected mice were treated with AmB or one of its derivatives, MS-8209, between 80 and 140 days postinoculation. We observed an increased incubation time and a delay in PrPres accumulation and glial fibrillary acidic protein gene expression. Treatment starting at 80 days postinoculation was as efficient as long-term treatment starting the day of inoculation. Our results indicate that polyene antibiotics may interfere, throughout the course of the experimental disease, with the propagation of the scrapie agent.


Asunto(s)
Anfotericina B/análogos & derivados , Polienos/farmacología , Scrapie/tratamiento farmacológico , Secuencia de Aminoácidos , Anfotericina B/farmacología , Animales , Antibacterianos/farmacología , Esquema de Medicación , Femenino , Ratones , Ratones Endogámicos C57BL , Datos de Secuencia Molecular , Proteínas PrPSc , Conejos , Scrapie/fisiopatología , Factores de Tiempo
9.
Expert Opin Investig Drugs ; 6(4): 345-8, 1997 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-15989603

RESUMEN

Creutzfeldt-Jakob disease (CJD) is a rare neurodegenerative illness which belongs to the group of transmissible subacute spongiform encephalopathies (TSSE). Today, no treatment is available for TSSE. The appearance of a new variant of CJD, which affects young people and could be linked to so-called ;mad cow disease', has stimulated researchers to develop new therapies against CJD. A few drugs have already been shown to delay the onset of experimental TSSE. They could contribute to the understanding of the pathogenic mechanisms involved in TSSE and, therefore, could be the basis for therapeutic strategies against CJD.

10.
Science ; 275(5298): 402-5, 1997 Jan 17.
Artículo en Inglés | MEDLINE | ID: mdl-8994041

RESUMEN

The agent responsible for transmissible spongiform encephalopathies (TSEs) is thought to be a malfolded, protease-resistant version (PrPres) of the normal cellular prion protein (PrP). The interspecies transmission of bovine spongiform encephalopathy (BSE) to mice was studied. Although all of the mice injected with homogenate from BSE-infected cattle brain exhibited neurological symptoms and neuronal death, more than 55 percent had no detectable PrPres. During serial passage, PrPres appeared after the agent became adapted to the new host. Thus, PrPres may be involved in species adaptation, but a further unidentified agent may actually transmit BSE.


Asunto(s)
Química Encefálica , Encefalopatía Espongiforme Bovina/transmisión , Proteínas del Tejido Nervioso/análisis , Priones/análisis , Animales , Apoptosis , Astrocitos/patología , Encéfalo/patología , Bovinos , Encefalopatía Espongiforme Bovina/metabolismo , Encefalopatía Espongiforme Bovina/patología , Endopeptidasas/metabolismo , Ratones , Ratones Endogámicos C57BL , Fenotipo , Células de Purkinje/patología , Pase Seriado , Factores de Tiempo , Vacuolas/patología
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA