Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0014070 (encephalomyelitis)
 13,017 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Impairment of the blood-brain barrier (BBB) in experimental autoimmune encephalomyelitis (EAE) has been frequently attributed to disruption, without much consideration of saturable transport processes. In mice with EAE, we studied the permeability of the BBB to radioactively labeled albumin and sucrose, markers of BBB disruption, and tumor necrosis factor-alpha (TNF-alpha), a cytokine transported across the BBB by a saturable system and thought to play a role in the pathogenesis of EAE. Permeation of the BBB was increased to all three substances during the acutely ill stage, was greatest in the lumbar spine, and returned to normal with recovery. The change in BBB permeability to sucrose was greater than to the larger albumin and is consistent with a partial disruption of the BBB. The enhanced permeability to TNF-alpha was comparable to that for sucrose, even though TNF-alpha is similar in size to albumin. This paradoxically high uptake of TNF-alpha could be explained by an enhancement of its endogenous saturable transport system. Thus the changes in BBB function during EAE extend beyond disruption to include changes in the saturable transport systems for substances involved in the disease process.
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PMID:Differential permeability of the BBB in acute EAE: enhanced transport of TNT-alpha. 889 50

Our goal was to test the effects of insulin-like growth factor I (IGF-I) treatment on clinical deficits, lesion number and lesion size in acute demyelinating experimental autoimmune encephalomyelitis (EAE) induced in Lewis rats with an emulsion containing guinea pig spinal cord. In this EAE model, there is severe immune-mediated demyelination, which resembles that seen in actively demyelinating MS lesions. On day 12-13 after EAE induction, a total of 23 pairs of rats with the same mild degree of tail and hind limb weakness were given either intravenous IGF-I or placebo twice daily for 8 days. The daily IGF-I dose used in the first trial was 200 micrograms (about 0.6 mg kg-1) and in the second and third trials was 1 mg (about 3.0 mg kg-1). IGF-I treatment reduced permeability of the blood-spinal cord barrier to Evans blue-albumin. Maximum clinical deficit scores of IGF-I-treated rats were significantly lower and treated rats recovered faster than controls. IGF-I treatment produced significant reductions in weight loss and hind limb weakness. Treatment also improved treadmill walking, stride length and climbing performance. Morphometric analysis showed that spinal cord inflammatory lesions were significantly smaller and fewer in IGF-I-treated rats. The higher IGF-I dose produced a greater reduction in clinical and pathological deficits. We conclude that IGF-I treatment promotes clinical recovery by reducing EAE-induced blood-spinal cord barrier changes and the associated immune-mediated inflammatory lesions. Our results suggest that IGF-I may be useful in treating patients with multiple sclerosis and other demyelinating diseases.
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PMID:Insulin-like growth factor I treatment reduces clinical deficits and lesion severity in acute demyelinating experimental autoimmune encephalomyelitis. 934 63

Breakdown of the blood-brain barrier (BBB) and ensuing gliosis are common events following physical trauma to the central nervous system (CNS) or during autoimmune diseases such as experimental allergic encephalomyelitis (EAE). Some studies of EAE in rodents report that peripheral injections of complete Freund's adjuvant (CFA), which contains heat-inactivated Mycobacterium to provoke peripheral inflammation without adversely affecting the CNS, can itself lead to increased BBB permeability to small tracer molecules and certain serum proteins. To study the equivocal relationship between serum protein extravasation and reactive gliosis, we injected C57BL/6 mice with CFA and histologically assessed the permeability of various serum proteins and the reactivity of proximal microglia and astrocytes in the uninjured brainstem and spinal cord enlargements after 1-4 weeks. Our results confirm that CFA injections induce progressive increases in the perivascular extravasation of serum IgG, albumin, IgM, and exogenous horseradish peroxidase, all to varying degrees, most prominently in the brainstem and cervical spinal cord after 2-3 weeks. More importantly, neither microglial cells nor astrocytes in regions of focal serum protein leakage appeared morphologically reactive based on immunoreactivity for CR3 receptors (Mac-1) or glial fibrillary acidic protein (GFAP), respectively. Because we found no evidence of T cell infiltration accompanying the exudates, our results indicate that in the absence of physical trauma or inflammatory cells resident CNS neuroglia remain quiescent upon exposure to extravasated serum proteins.
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PMID:Peripheral injections of Freund's adjuvant in mice provoke leakage of serum proteins through the blood-brain barrier without inducing reactive gliosis. 1037 54

Cerebrospinal fluid (CSF) was removed from guineapigs by puncture of the cisterna magna and the total sample volume of 200-360 microl divided into 40 microl aliquots. After determination of albumin and IgG in these CSF aliquots it was found that successive samples gave different results. In general, up to 100 microl CSF could be removed before the protein concentration began to increase. In animals with chronic relapsing experimental allergic encephalomyelitis (CR-EAE) the rise in albumin concentration was accompanied by a corresponding fall in the number of white cells in later samples.
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PMID:Cerebrospinal fluid sampling from guineapigs: sample volume--related changes in protein concentration in control animals and animals in the relapsing phase of chronic relapsing experimental allergic encephalomyelitis. 1062 84

Experimental allergic encephalomyelitis (EAE) is an autoimmune disease characterised by a disruption of the blood-brain barrier (BBB), demyelination and a relevant inflammatory reaction with an intense infiltration of macrophages. These neurological disorders are similar to those observed in the multiple sclerosis (MS) disease. The use of different liposomes and adeno-associated virus has been proposed for improving the treatment of this pathogenesis. The aim of this work was to evaluate the potential and capacity of albumin nanoparticles to reach the central nervous system (CNS) in EAE-induced rats. For this purpose, the distribution of biotinylated nanoparticles within the CNS was studied. Albumin carriers were mainly found in the lumbar portion of the spinal cord, overlying the meningeal and perivascular areas. The optic chiasma, iris and the area of the Purkinje cells of the cerebellum revealed also an intense presence of these carriers. Finally, immunohistochemical studies also revealed that circulating macrophages (ED1), which migrate to damaged sites, and resident activated microglial cells (OX42) were involved in the distribution of albumin nanoparticles. In summary, the use of nanoparticles may be useful for the design of new pharmaceutical dosage forms able to target the lesions associated with alterations of the BBB.
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PMID:Distribution of albumin nanoparticles in animals induced with the experimental allergic encephalomyelitis. 1132 57

We investigated the possible mechanisms how interferon (IFN)-beta may control T cell infiltration in the CNS in experimental autoimmune encephalomyelitis (EAE). Adoptive transfer (AT) EAE was induced in groups of six female Lewis rats. Animals were treated with 3 x 10(5) units of recombinant rat IFN-beta s.c. once at 18 hr, or with 10 mg/kg methylprednisolone (MP) i.v. twice at 18 and 6 hr prior to dissection, or with a combination of both. T cell apoptosis was detected by immunohistochemistry on paraffin sections of spinal cord, using morphological criteria and TUNEL staining. Double labeling of immune cells was done for tumor necrosis factor (TNF)-alpha and metalloproteinase (MMP) 2. Disruption of the blood-brain barrier (BBB) was visualized by staining for albumin. In severe EAE, an increase of T cell apoptosis was seen after IFN-beta alone (all data presented as mean +/- SD: 24.5% +/- 2.2%, P < 0.05, vs. 19.4% +/- 3.1% in controls), and in combination with MP (29.4% +/- 7.3%, P < 0.05 vs. controls). Only the combination therapy decreased T cell infiltration (53.9 +/- 17.7 cells/mm(2), P < 0.05, vs. 99.5 +/- 35.2 cells/mm2 in controls). In moderate EAE, the rate of T cell apoptosis was slightly increased after IFN-beta (21.2% +/- 5.2% vs. 17.4% +/- 5.0% in controls), whereas MP alone (25.5% +/- 3.5%, P < 0.01 vs. controls) and the combination therapy (22.4% +/- 4.8%, P < 0.05 vs. controls) had a clear augmenting effect. IFN-beta tended to decrease T cell infiltration (46.1 +/- 12.7 cells/mm2) compared to controls (59.2 +/- 18.5 cells/mm2). The rate of TNF-alpha-expressing T cells was significantly decreased by IFN-beta and in combination with MP. Also, TNF-alpha expression in macrophages was significantly reduced by IFN-beta and by the combination therapy. The rate of MMP2-expressing macrophages was lower after IFN-beta but clearly decreased only in combination with MP. BBB disruption was ameliorated after IFN-beta but significantly only in combination with MP. Our study indicates that IFN-beta affects the immunopathological process in EAE in several ways, but apoptosis appears as a minor component. In view of treatment of MS relapses, the synergistic effects in this study corroborate the use of a combination therapy with high-dose MP and IFN-beta.
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PMID:Interferon-beta treatment of experimental autoimmune encephalomyelitis leads to rapid nonapoptotic termination of T cell infiltration. 1143 30

The transport system for the cytokine tumor necrosis factor-alpha (TNFalpha) at the blood-brain barrier (BBB) enables an enhanced yet saturable entry of TNFalpha from blood to the CNS. This review focuses on the selective upregulation of the transport system for TNFalpha at the BBB that is specific for type of pathology, region, and time. The upregulation is reflected by increased CNS tissue uptake of radiolabeled TNFalpha after iv injection in mice and by inhibition of this increase with excess non-radiolabeled TNFalpha. (1) Spinal cord injury (SCI): upregulation of TNFalpha uptake after thoracic transection is seen in the delayed phase of BBB disruption at the lumbar spinal cord. Thoracic SCI by compression, however, has a longer lasting impact on TNFalpha transport that involves thoracic and lumbar spinal cord, in contrast to the upregulation confined to the lumbar region in lumbar SCI by compression. Regardless, the uptake of TNFalpha by spinal cord does not parallel BBB disruption as measured by the leakage of radiolabeled albumin. (2) Experimental autoimmune encephalomyelitis (EAE): the increase in the differential permeability to TNFalpha is seen in all CNS regions (brain and cervical, thoracic, and lumbar spinal cord) and has a distinct time course and reversibility. Exogenous TNFalpha has biphasic effects in modulating functional scores. The BBB, a dynamically regulated barrier, is actively involved in disease processes.
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PMID:Upregulation of the transport system for TNFalpha at the blood-brain barrier. 1193 70

Tumor necrosis factor (TNF-alpha) and IL-10 are key regulators of the T helper (Th)1/Th2 balance, which is critically skewed in many pathological conditions including immune-mediated inflammatory diseases of central nervous system (CNS) such as multiple sclerosis (MS). Nitric oxide (NO) has been reported to have dual effects on CNS pathology, and to play an important role in MS. We performed a cross-sectional study in 17 randomly selected patients during MS flare-up, and compared levels of TNF-alpha, IL-10 and NO in serum and cerebrospinal fluid (CSF) with the serum values of these mediators in two different control groups, healthy subjects and HIV-infected untreated patients. Serum and CSF values of TNF-alpha, IL-10 and NO were higher in MS patients than in the serum of healthy controls. Two MS patients showed increased levels of NO in CSF, with inversion of the NO(SERUM)/NO(CSF) quotient, which is clearly indicative of an intrathecal production of NO. No correlation among the values of both cytokines and NO, and the laboratory parameters analysed in MS patients (IgG index, presence of IgG oligoclonal bands and albumin quotient) was found. The high levels of TNF-alpha and IL-10 (both in serum and CSF) accompanying an MS attack suggest a simultaneous expression of Th1 and Th2 cytokines as opposed to sequential expression of Th1 followed by Th2 as described in the models of experimental autoimmune encephalomyelitis (EAE). Globally, our results support the inherent heterogeneity of the disease.
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PMID:Th1/Th2 cytokine balance and nitric oxide in cerebrospinal fluid and serum from patients with multiple sclerosis. 1195 29

Experimental allergic encephalomyelitis (EAE), a model of multiple sclerosis, is an autoimmune, demyelinating disease of the CNS. Pro-inflammatory cytokines (e.g. tumour necrosis factor-alpha (TNF-alpha) and interleukin (IL)-12) and reactive oxygen species are implicated in promoting EAE. Since histamine H(2) receptor activation suppresses production of O(2)*-, TNF-alpha, and IL-12 by inflammatory cells, we tested the hypothesis that dimaprit, an H(2) agonist, would reduce the clinical severity and pathology of EAE. Dimaprit treatment significantly reduced clinical signs compared to vehicle in both C57BL/6 and iNOS deficient EAE mice. Furthermore, dimaprit significantly reduced CNS staining for lectin-positive macrophages and decreased extravasated albumin staining, an indicator of blood-brain barrier leakage. These data provide a rationale for exploring H2 receptor activation for therapeutic value in multiple sclerosis.
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PMID:Activation of histamine H2 receptors ameliorates experimental allergic encephalomyelitis. 1216 63

A neutral protease present in inguinal and popliteal lymph nodes of rats with acute experimental allergic encephalomyelitis (EAE), rats injected with Freund's adjuvant, and rats that are normal has been found to hydrolyze basic protein present in purified brain and spinal cord myelin. The enzyme has been enriched by ammonium sulfate precipitation, and its properties have been studied. The protease activity toward different substrates was very specific and decreased in the following order: Protamine sulfate = polylysine (MW 183,000) > myelin basic protein > histone > polylysine (MW 2000) > polyarginine > cytochrome c. Other proteins including casein, freshly denatured hemoglobin, egg albumin, bovine serum albumin, and ribonuclease were ineffective as substrates. The pH curve showed a peak at pH7 for rat myelin, isolated beef basic protein, and histone. A possible role for this enzyme in demyelination in acute experimental allergic encephalomyelitis is suggested.
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PMID:A lymph node neutral proteinase acting on myelin basic protein. 1217 May 91


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