Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human interferon (IFN) beta is the first therapeutic agent to convincingly reduce the multiple sclerosis relapse rate and retard disability. To achieve this significant treatment advance over 15 years of preliminary work was necessary, encompassing over 15 controlled trials which employed each of the three human interferons. Important insights into the pathogenesis of multiple sclerosis (MS) were gained, especially from the findings of the single IFN-gamma trial. This short history describes the unfolding of our current understanding of the place for IFNs in the management of MS. The contribution of the patients who have participated is recognized and their courage acknowledged. The final role for IFN treatment of MS is unclear, but future studies will be required to define the best IFN, optimal dose, and route of administration and patient selection for long-term management of MS.
J Mol Med (Berl) 1997 Feb
PMID:The historical development of interferons as multiple sclerosis therapies. 908 26

Multiple sclerosis is an autoimmune disease with inflammatory lesions localized to the white matter of the central nervous system. Early on, the disease is characterized by episodes of exacerbations and remissions. During exacerbations there is an acute inflammatory infiltrate characterized by the presence of mononuclear cells, monocytes, and T lymphocytes. These cells produce proinflammatory cytokines that have been implicated in the amplification of the inflammatory response as well as in the damage of oligodendrocytes. The inflammation ultimately results in loss of myelin and oligodendrocyte cell death (demyelination). Thus therapies aimed at preventing the inflammatory response may have a beneficial effect on the course of the disease. One such therapy is treatment with inhibitors of phosphodiesterase type IV. These drugs have proven to be extremely effective in the prevention and treatment of experimental allergic encephalomyelitis, the animal model for multiple sclerosis. These experiments, as well as other data discussed here, provide a rationale for the treatment of multiple sclerosis with inhibitors of phosphodiesterase type IV.
J Mol Med (Berl) 1997 Feb
PMID:Phosphodiesterase type IV inhibitors in the treatment of multiple sclerosis. 908 27

One of the characteristic features of microglia is their rapid activation in response to injury, inflammation, neurodegeneration, infection, and brain tumors. This review focuses on the role of the microglia in multiple sclerosis (MS), a chronic inflammatory demyelinating disease of the central nervous system (CNS), and in the animal model of MS, experimental allergic encephalomyelitis (EAE). Microglial activation in MS and EAE is thought to contribute directly to CNS damage through several mechanisms, including production of proinflammatory cytokines, matrix metalloproteinases, and free radicals. In addition, activated microglia serve as the major antigen-presenting cell in the CNS, likely contributing to aberrant immune reactivity at this site. A mechanistic understanding of the way in which microglia are activated and ultimately inhibited is crucial for the formulation of therapeutic modalities to treat MS and other CNS autoimmune disease.
J Mol Med (Berl) 1997 Mar
PMID:Role of macrophages/microglia in multiple sclerosis and experimental allergic encephalomyelitis. 910 72

During the past decade nitric oxide has emerged as an important mediator of physiological and pathophysiological processes. Elevated nitric oxide bio-synthesis has been associated with nonspecific immune-mediated cellular cytotoxicity and the pathogenesis of chronic, inflammatory autoimmune diseases including rheumatoid arthritis, insulin-dependent diabetes, inflammatory bowel disease, and multiple sclerosis. Recent evidence suggests, however, that nitric oxide is also immunoregulatory and suppresses the function of activated proinflammatory macrophages and T lymphocytes involved in these diseases. This article reviews the role of nitric oxide in the biology of central nervous system glial cells (astrocytes and microglia) as it pertains to the pathogenesis of multiple sclerosis in humans and experimental allergic encephalitis, the animal model of this disease. Although nitric oxide has been clearly implicated as a potential mediator of microglia-dependent primary demyelination, a hallmark of multiple sclerosis, studies with nitric oxide synthase inhibitors in the encephalitis model have been equivocal. These data are critically reviewed in the context of what is know from clinical research on the nitric oxide pathway in multiple sclerosis. Specific recommendations for future preclinical animal model research and clinical research on the nitric oxide pathway in patients are suggested. These studies are necessary to further define the role of nitric oxide in the pathology of multiple sclerosis and to fully explore the potential for nitric oxide synthase inhibitors as novel therapeutics for this disease.
J Mol Med (Berl) 1997 Mar
PMID:The role of nitric oxide in multiple sclerosis. 910 72

Multiple sclerosis (MS) is an inflammatory disease of the CNS white matter characterized pathologically by the accumulation of perivascular and parenchymal T lymphocytes (T cells), and macrophage infiltration associated with myelin destruction. MS lesions are also characterized by the death of oligodendrocytes (the myelin-producing cells) and proliferation and hypertrophy of astrocytes with scar tissue (gliosis) replacing normal myelin. These changes result in the loss of axonal conduction for neurons of the CNS and in clinical disability. MS is thought to be an autoimmune disease, in particular because of its analogy with the disease model of experimental allergic encephalomyelitis (EAE). Despite extensive research and the availability of various EAE models in laboratory rodents the etiology of human MS has not been identified, and to date no effective treatment exists. Phylogenetic differences may limit the usefulness of existing EAE models, and indeed no single form of rodent EAE recapitulates all the clinical and pathological features of MS. Here we describe a novel form of EAE created in a nonhuman primate, the common marmoset Callithrix jacchus. Active immunization of these monkeys with whole myelin produces a primary demyelinating disease with a chronic relapsing-remitting course, characterized pathologically by moderate inflammation with prominent and early demyelination and gliosis reminiscent of human MS. Adoptive and passive transfer experiments have permitted definition of the mechanisms responsible for the MS-like pathology. Production of the fully demyelinated lesion requires synergism between encephalitogenic (e.g., disease-inducing) T cells and pathogenic antibody. The antigens of myelin that promote encephalitogenic T cell and antibody responses in this system have been identified. Because of the similarity between the two conditions and the high degree of conservation in immune and nervous system genes between nonhuman primates and humans, future studies of marmoset EAE will likely accelerate the development of therapies for human MS.
J Mol Med (Berl) 1997 Mar
PMID:Creation of a model for multiple sclerosis in Callithrix jacchus marmosets. 910 72

Copolymer 1 (Cop-1) is a synthetic amino acid copolymer effective in suppression of experimental allergic encephalomyelitis (EAE). The suppressive effect of Cop-1 in EAE is a general phenomenon and is not restricted to a particular species, disease type or encephalitogen used for EAE induction. In phase III clinical trials Cop-1 was found to slow progression of disability and reduce the relapse rate in exacerbating-remitting multiple sclerosis (MS). In vivo and in vitro studies suggest that the mechanism for Cop-1 activity in EAE and MS involves the binding of Cop-1 to major histocompatibility complex class II molecules as an initial step. This binding results both in competition with myelin antigens for T-cell activation and in induction of specific suppressor cells of the Th2 type. As an antigen-specific intervention, Cop-1 has the advantage of reduced probability of long-term damage to the immune system.
Cell Mol Life Sci 1997 Jan
PMID:Copolymer 1: from basic research to clinical application. 911 94

T-cell receptor (TCR) delta gene repertoire, as assessed by V delta-J delta rearrangements, has been analyzed in nine multiple sclerosis (MS) cases and in 30 healthy individuals by seminested PCR technique. Among the V delta-J delta junctional diversities studied, the most striking result has been observed in V delta 5-J delta 1 rearrangement. The detection of repeated V delta 5-J delta 1 nucleotide sequences in all analyzed clones from seven out of nine patients studied proved the monoclonal nature of gamma delta T-cells with V delta 5-J delta 1 rearrangement. The clonal nature of this rearrangement proved by PAGE and sequencing analysis may suggest an antigen-driven expansion of gamma delta T cells and argues for a significant role of gamma delta T-cells with V delta 5-J delta 1 rearrangement in MS pathogenesis. However, it cannot be excluded that clonal expansion of these lymphocytes may represent secondary change to central nervous system damage.
Mol Chem Neuropathol
PMID:Limited junctional diversity of V delta 5-J delta 1 rearrangement in multiple sclerosis patients. 913 31

Dysthymia is characterized by long-lasting periods of lowered mood. Epidemiological studies in the USA and Europe have demonstrated that the prevalence of dysthymia is at least 3% of the general population. Its pervasive occurrence makes dysthymia a public health problem worldwide. One feature of this disorder is its co-occurrence with medical and neurological disorders. A World Health Organization meeting on dysthymia in neurological disorders was held in Geneva, 1-3 July 1996 to address this topic. Some of the major goals of this meeting were to clarify the definition of dysthymia in the presence of neurological disorders and to evaluate current research in the field, to point out new areas for investigation, and to discuss current psychological and pharmacological treatments for dysthymia in neurological disorders. The potential roles of neuroendocrine and molecular mechanisms in dysthymia were identified through specific problems related to dysthymia occurring in disorders such as Parkinson's disease, Alzheimer's disease, stroke, multiple sclerosis and epilepsy. This meeting provided direction and opportunity for future studies in the under-recognized and under-investigated relationship between dysthymia and neurological disorders.
Mol Psychiatry 1996 Dec
PMID:Dysthymia in neurological disorders. 915 50

Spinal cord white matter is the major site of tissue damage resulting from decompression sickness (DCS or "the bends"). Damage is thought to result from bubble nucleation within the tissue. Why DCS occurs predominantly in the spinal cord and not in the brain is not known; neither is the exact pathological mechanism by which the spinal cord is damaged, nor how multiple sclerosis (MS)-like symptoms may ensue. To investigate the molecular basis of white matter damage, we subjected myelinated mouse tissues to varying durations of decompression, and then after recompression to one atmosphere, examined them for changes in myelin structure and composition. X-ray diffraction showed that the myelin period in spinal cord decreased by 4%, whereas those of optic and sciatic nerves were stable. The change in period was accompanied by a change in membrane bilayer profile--i.e., relative to control, the width of the bilayer decreased by approximately 6 A, whereas the interbilayer spaces each increased by approximately 3 A. The changes in electron density levels suggested a redistribution of matter from the interbilayer spaces into the lipid headgroup layers. By contrast with these structural changes, sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and high-performance thin layer chromatography (HPTLC) revealed no noticeable change in myelin composition--i.e., there was no release of myelin-specific proteins or lipids. Our findings indicate that spinal cord myelin has an inherent structural vulnerability that may facilitate the targeting of this tissue during pressure changes.
Mol Chem Neuropathol 1997 Apr
PMID:Spinal cord myelin is vulnerable to decompression. 916 91

Interferon-gamma (IFN-gamma) is a pleotropic cytokine released by T-lymphocytes and natural killer cells. Normally, these cells do not traverse the blood-brain barrier at appreciable levels and, as such, IFN-gamma is generally undetectable within the central nervous system (CNS). Nevertheless, in response to CNS infections, as well as during certain disorders in which the CNS is affected, T-cell traffic across the blood-brain barrier increases considerably, thereby exposing neuronal and glial cells to the potent effects of IFN-gamma. A larger portion of this article is devoted to the substantial circumstantial and experimental evidence that suggests that IFN-gamma plays an important role in the pathogenesis of the demyelinating disorder multiple sclerosis (MS) and its animal model experimental allergic encephalomyelitis (EAE). Moreover, the biochemical and physiological effects of IFN-gamma are discussed in the context of the potential consequences of such activities on the developing and mature nervous systems.
Mol Neurobiol
PMID:The effects of interferon-gamma on the central nervous system. 917 99


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