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2.
Bioorg Med Chem ; 9(2): 537-54, 2001 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-11249145

RESUMO

RPR132331, a 2-(2-dioxanyl)imidazole, was identified as an inhibitor of tumour necrosis factor (TNF)alpha release from lipopolysaccharide (LPS)-stimulated human monocytes. An intensive programme of work exploring the biology, toxicity and physical chemistry of a novel series of inhibitors, derived from RPR132331, has led to the identification of RPR200765A, a development candidate for the treatment of rheumatoid arthritis (RA). RPR200765A is a potent and selective inhibitor of p38 MAP kinase (IC50 = 50 nM). It inhibits LPS-stimulated TNFalpha release both in vitro, from human monocytes (EC50 = 110 nM), and in vivo in Balb/c mice (ED50 = 6 mg/kg). At oral doses between 10 and 30 mg/kg/day it reduces the incidence and progression in the rat streptococcal cell wall (SCW) arthritis model when administered in either prophylactic or therapeutic dosing regimens. The compound, which is a mesylate salt and exists as a stable monohydrate, shows good oral bioavailabiltiy (F = 50% in the rat) and excellent chemical stability. The data from the SCW disease model suggests that RPR200765A could exhibit a profile of disease modifying activity in rheumatoid arthritis (RA) patients which is not observed with current drug therapies.


Assuntos
Antirreumáticos/síntese química , Antirreumáticos/farmacocinética , Imidazóis/farmacologia , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Administração Oral , Animais , Antirreumáticos/farmacologia , Artrite/induzido quimicamente , Artrite/tratamento farmacológico , Artrite/prevenção & controle , Disponibilidade Biológica , Citocromo P-450 CYP1A1/efeitos dos fármacos , Citocromo P-450 CYP1A1/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Estabilidade de Medicamentos , Indução Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/farmacologia , Feminino , Humanos , Imidazóis/síntese química , Concentração Inibidora 50 , Lipopolissacarídeos/farmacologia , Camundongos , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno
3.
J Neuroimmunol ; 106(1-2): 130-6, 2000 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-10814790

RESUMO

There is circumstantial evidence implicating the pro-inflammatory cytokine tumour necrosis factor (TNF) in the pathogenesis of multiple sclerosis (MS), but there is no direct evidence that TNF can produce demyelination in the central nervous system (CNS). We demonstrate here that single injections of TNF into the dorsal columns of adult rats produced a mild inflammatory response indistinguishable from that seen in control cords, but did not induce demyelination. A similar response was seen when TNF-alpha was injected into dorsal columns where central axons had been remyelinated by Schwann cells. In marked contrast, single intraneural injections of TNF into sciatic nerves produced acute changes in the endoneurial microvascular bed that were followed by demyelination and degeneration.


Assuntos
Nervos Periféricos/efeitos dos fármacos , Nervos Periféricos/patologia , Medula Espinal/efeitos dos fármacos , Medula Espinal/patologia , Fator de Necrose Tumoral alfa/farmacologia , Animais , Etídio/farmacologia , Injeções , Injeções Espinhais , Masculino , Ratos , Ratos Sprague-Dawley , Nervo Isquiático/fisiologia
4.
Brain ; 121 ( Pt 3): 481-94, 1998 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-9549524

RESUMO

Experimental autoimmune neuritis (EAN) is an animal model of Guillain-Barré syndrome. We have shown recently that BB-1101, a broad-spectrum matrix metalloproteinase (MMP) inhibitor, prevents development of EAN when given from the day of immunization and, more important clinically, reduces disease severity when given from symptom onset. This suggests the involvement of MMP activity in the pathogenesis of EAN. However, the exact function and expression patterns of MMPs in acute inflammation of the PNS have not been investigated. MMP-like enzymes are also involved in the processing of tumour necrosis factor-alpha (TNF-alpha), which has been implicated previously in the pathology associated with EAN. In the present study we investigated the profile of MMP and TNF-alpha expression and their localization in sciatic nerve tissue during EAN, using a semiquantitative competitive reverse transcriptase-coupled polymerase chain reaction and immunohistochemistry. In the normal rat PNS, four of the 10 MMPs studied were constitutively expressed and four MMPs were differentially regulated during EAN. Expression of TNF-alpha was elevated at peak disease severity and localized to Schwann cells, macrophages and endoneurial blood vessels. Expression levels of 92 kDa gelatinase and stromelysin-1 were significantly increased early in the development of EAN and continued to rise, peaking at day 15 coincident with maximum disease severity. Schwann cells and endothelial cells were the main cellular source of these enzymes. Prominent infiltration of inflammatory cells into the sciatic nerve was concordant with a significant increase in the expression levels of matrilysin and macrophage metalloelastase. Both matrilysin and macrophage metalloelastase were detected in invading macrophages, T lymphocytes and resident Schwann cells. The selective upregulation of specific MMPs during EAN and their varied cellular localization suggests that MMPs play a multifactorial role in the aetiology of EAN. Activity of MMPs could participate in the disruption of the blood-nerve barrier, breakdown of the myelin sheath, the release of TNF-alpha, and facilitate leukocyte invasion into the PNS. These observations highlight MMPs as potential targets for therapeutic intervention in acute peripheral neuropathies, such as Guillain-Barré syndrome.


Assuntos
Doenças Autoimunes/metabolismo , Metaloendopeptidases/metabolismo , Neurite (Inflamação)/metabolismo , Animais , Imuno-Histoquímica , Metaloendopeptidases/genética , Reação em Cadeia da Polimerase , Ratos , Ratos Endogâmicos Lew , Valores de Referência , Nervo Isquiático/metabolismo , Distribuição Tecidual , Transcrição Gênica , Fator de Necrose Tumoral alfa/metabolismo
5.
Brain ; 120 ( Pt 10): 1895-905, 1997 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-9365379

RESUMO

Matrix metalloproteinases (MMPs) and the cytokine tumour necrosis factor (TNF)-alpha are implicated in the pathology of inflammatory demyelinating diseases of the CNS, and may also be involved in peripheral demyelinating diseases such as acute inflammatory demyelinating polyradiculoneuropathy. We have tested an inhibitor of MMP activity and TNF-alpha processing, BB-1101, in experimental autoimmune neuritis (EAN), an animal model of Guillain-Barré syndrome. Treatment with BB-1101 from the time of immunization prevented the development of EAN, and when given from the onset of symptoms, it significantly reduced disease severity. These results indicate that MMPs and/or TNF-alpha are involved in the pathogenesis of EAN, and that drugs of this type may have potential as novel therapeutic agents in the therapy of peripheral nervous system demyelinating diseases.


Assuntos
Dexametasona/farmacologia , Matriz Extracelular/enzimologia , Metaloendopeptidases/antagonistas & inibidores , Neurite Autoimune Experimental/fisiopatologia , Pentoxifilina/farmacologia , Inibidores de Proteases/farmacologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Animais , Compostos de Benzil , Combinação de Medicamentos , Feminino , Gelatinases/metabolismo , Imuno-Histoquímica , Masculino , Neurite Autoimune Experimental/prevenção & controle , Ratos , Ratos Endogâmicos Lew , Nervo Isquiático/enzimologia , Succinatos , Distribuição Tecidual
6.
Brain ; 120 ( Pt 9): 1533-40, 1997 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-9313637

RESUMO

Human immunoglobulin is an effective treatment for Guillain-Barré syndrome, although the mechanism of action is not understood. We have investigated the effect of human immunoglobulin in an animal model of Guillain-Barré syndrome, namely experimental autoimmune neuritis (EAN), induced in Lewis rats by immunization with bovine spinal root myelin. Human immunoglobulin administered intraperitoneally at the time of onset of disease accelerated the rate of recovery from EAN. This improvement was associated with a reduction in the titre of anti-rat myelin antibodies and may be due to earlier remyelination of demyelinated nerve fibres. This model may facilitate further investigation of the mechanism of therapeutic action of immunoglobulin in inflammatory neuropathy.


Assuntos
Imunização Passiva , Neurite Autoimune Experimental/terapia , Animais , Anticorpos/análise , Formação de Anticorpos , Bovinos , Cauda Equina/ultraestrutura , Humanos , Masculino , Microscopia Eletrônica , Bainha de Mielina/imunologia , Neurite Autoimune Experimental/imunologia , Neurite Autoimune Experimental/patologia , Ratos , Ratos Endogâmicos Lew , Raízes Nervosas Espinhais/imunologia
7.
Brain ; 120 ( Pt 12): 2149-57, 1997 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-9448570

RESUMO

Diseases such as multiple sclerosis and Guillain-Barré syndrome are characterized not only by widespread loss of myelin from nerve fibres, but also by widespread inflammation in the central and peripheral nervous systems, respectively. While the demyelination alone is sufficient to block conduction and thereby cause symptoms, there is increasing evidence that the inflammation may also contribute significantly to the conduction block, although the mechanisms are not understood. Nitric oxide is an important inflammatory mediator which is elevated within the central nervous system in multiple sclerosis and which can be experimentally applied to tissues using nitric oxide donors. We report that such compounds cause reversible conduction block in both normal and demyelinated axons of the central and peripheral nervous systems. Notably, conduction in demyelinated and early remyelinated axons is particularly sensitive to block by nitric oxide, so that at lower concentrations, including those expected at sites of inflammation, demyelinated axons are selectively affected. We therefore propose that inflammation may directly cause symptoms via nitric oxide release, and that the inhibition of such release may open a new therapeutic avenue for demyelinating disease.


Assuntos
Axônios/fisiologia , Bainha de Mielina/fisiologia , Condução Nervosa/efeitos dos fármacos , Óxido Nítrico/farmacologia , Nervos Periféricos/fisiologia , Medula Espinal/fisiologia , Animais , Axônios/efeitos dos fármacos , Bovinos , Doenças Desmielinizantes/fisiopatologia , Etídio/administração & dosagem , Etídio/farmacologia , Lisofosfatidilcolinas/administração & dosagem , Lisofosfatidilcolinas/farmacologia , Microinjeções , Mycobacterium tuberculosis , Neurite Autoimune Experimental/fisiopatologia , Óxidos de Nitrogênio , Penicilamina/análogos & derivados , Penicilamina/farmacologia , Nervos Periféricos/efeitos dos fármacos , Nervo Fibular/fisiologia , Ratos , Ratos Endogâmicos Lew , Ratos Sprague-Dawley , S-Nitroso-N-Acetilpenicilamina , Nervo Isquiático/fisiologia , Espermina/análogos & derivados , Espermina/farmacologia , Medula Espinal/efeitos dos fármacos , Nervo Tibial/fisiologia
8.
Brain ; 118 ( Pt 4): 869-78, 1995 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-7655885

RESUMO

Several observations suggest that tumour necrosis factor (TNF) plays a role in demyelination, although direct evidence for this is lacking. We have examined ultrastructurally rat sciatic nerves injected with TNF-alpha or TNF-beta: the effects of the two cytokines were found to be qualitatively similar. One day after injection nerves were oedematous and contained many inflammatory cells. Leucocytes were adherent to the walls of endoneurial vessels and sometimes were packed into the sub-endothelial layer apparently occluding the vascular lumen. Occasional myelinated axons were associated with macrophages and showed signs of myelin damage. By 3 days the inflammatory changes had diminished: some axons were degenerating or demyelinating. By 6-7 days, the vascular changes had resolved, and the endoneurium contained significant numbers of demyelinating and degenerating axons. Control nerves, which received injections of vehicle, showed no vascular changes and either no, or significantly fewer, degenerating or demyelinating axons. We conclude that the intraneural injection of TNF produces inflammatory vascular changes within the endoneurium, together with demyelination and axonal degeneration. We have also observed demyelination and degeneration in a preliminary study of the effects of TNF-alpha in mice. These findings may be relevant to the pathogenesis of demyelinating diseases such as Guillain-Barré syndrome.


Assuntos
Doenças Desmielinizantes/patologia , Bainha de Mielina/efeitos dos fármacos , Bainha de Mielina/patologia , Nervo Isquiático/irrigação sanguínea , Fator de Necrose Tumoral alfa/farmacologia , Animais , Doenças Desmielinizantes/etiologia , Masculino , Camundongos , Neurite (Inflamação)/etiologia , Neurite (Inflamação)/patologia , Ratos , Ratos Sprague-Dawley , Nervo Isquiático/patologia , Fator de Necrose Tumoral alfa/fisiologia
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