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)

Gelatinases, belonging to the matrix metalloproteases, contribute to tissue destruction in inflammatory demyelinating disorders of the central nervous system such as multiple sclerosis. We used experimental autoimmune encephalomyelitis (EAE) as an animal model to evaluate the effect of a hydroxamate matrix metalloprotease inhibitor (GM 6001) on inflammatory demyelination. A single dose of the inhibitor, given intraperitoneally, provided sufficient levels in the cerebrospinal fluid of animals with EAE to induce at least a partial inhibition of the gelatinase activity in the cerebrospinal fluid. When administered daily either from the time of disease induction or from the onset of clinical signs, GM 6001 suppressed the development or reversed clinical EAE in a dose-dependent way, respectively. Animals returned to the same clinical course as the nontreated group after cessation of treatment. Animals treated from the onset of clinical signs had normal permeability of the blood-brain barrier, compared with the enhanced permeability in nontreated animals. These results indicate that matrix metalloprotease inhibition can reverse ongoing EAE. This effect appears to be mediated mainly through restoration of the damaged blood-brain barrier in the inflammatory phase of the disease, since, the degree of demyelination and inflammation did not differ between the treatment groups.
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PMID:Reversal of experimental autoimmune encephalomyelitis with a hydroxamate inhibitor of matrix metalloproteases. 798 72

Experimental autoimmune encephalomyelitis (EAE) is an animal model of inflammatory demyelination, a pathological event common to multiple sclerosis (MS). During CNS inflammation there are alterations in the extracellular matrix (ECM). A Disintegrin and Metalloproteinase with Thrombospondin motifs (ADAMTS)-1, -4 and -5 are proteases present in the CNS, which are able to cleave the aggregating chondroitin sulphate proteoglycans, aggrecan, phosphacan, neurocan and brevican. It is therefore important to investigate changes in their expression in different stages of EAE induction. We have investigated expression of ADAMTS-1, -4, -5 and tissue inhibitor of metalloproteinase (TIMP)-3, by real-time RT-PCR. We have also examined protein expression of ADAMTS-1, -4 and -5 by western blotting and immunocytochemistry in spinal cord from animals at different stages of disease progression. Our study demonstrated a decrease in ADAMTS-4 mRNA and protein expression. TIMP-3 was decreased at the mRNA level although protein levels were increased in diseased animals compared to controls. Our study identifies changes in ADAMTS expression during the course of CNS inflammation which may contribute to ECM degradation and disease progression.
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PMID:Differential expression of ADAMTS-1, -4, -5 and TIMP-3 in rat spinal cord at different stages of acute experimental autoimmune encephalomyelitis. 1630 87

Multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE) are both characterized by the infiltration of myelin-reactive T cells that trigger oligodendrocyte death associated with axonal loss and neurodegeneration in the CNS. Proteolysis of the cerebral vascular extracellular matrix (ECM) resulting in blood-brain barrier (BBB) breakdown is thought to facilitate infiltration of autoreactive T cells in both of these demyelinating disorders. Increased matrix metalloprotease (MMP) activity coupled with reduced levels of tissue inhibitor of metalloproteases (TIMPs) contribute to a loss of BBB integrity. Erythropoietin induces expression of TIMP-1 in endothelial cells suggesting this property may account in part for its ability to maintain BBB integrity and efficacy in a preliminary clinical MS trial. Consistent with this hypothesis, we report here that administration of the erythropoietin analogue darbepoetin alfa at a low dose that did not elevate hematocrit reduced EAE severity in female C57BL/6 mice when administered following the onset of clinical signs. The protective effects of darbepoetin alfa were associated with an increase in the number of astrocytes expressing TIMP-1 in the brain and spinal cord. In keeping with a central role for TIMP-1 in this autoimmune model of acute demyelination, TIMP-1 null mice displayed a more severe EAE phenotype than wild-type littermates. Interestingly, we observed a lack of effect of darbepoetin alfa on EAE severity in TIMP-1 null mice. These findings indicate that TIMP-1 deficiency both enhances disease severity and attenuates the beneficial effects of low dose darbepoetin alfa in a mouse model of EAE.
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PMID:Lack of TIMP-1 increases severity of experimental autoimmune encephalomyelitis: Effects of darbepoetin alfa on TIMP-1 null and wild-type mice. 1942 25

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS), and experimental autoimmune encephalomyelitis (EAE) is a well-established animal model of the disease. Here, we examined the pathophysiological role of Kallikrein 6 (Klk6), a serine protease produced by oligodendrocytes (OLs), in EAE using Klk6 knockout (Klk6-/-) mice. Compared with Klk6+/+ (wild-type) mice, Klk6-/- mice showed milder EAE symptoms, including delayed onset and milder paralysis. Loss of Klk6 suppressed matrix metalloprotease-9 expression and diminished the infiltration of peripheral inflammatory cells into the CNS by decreasing blood-brain barrier (BBB) permeability and reducing expression levels of inflammatory cytokines, chemokines and their receptors. Scanning electron microscopic analysis revealed demyelination characterized by myelin detachment from the axons in the early phase of EAE progression (days 3-7) in Klk6+/+ mice but not in Klk6-/- mice. Interestingly, anti-MOG (myelin oligodendrocyte glycoprotein) autoantibody was also detected in the cerebrospinal fluid (CSF) and spinal cord on day 3 after MOG immunization. Furthermore, treatment of primary cultured OLs with anti-MOG autoantibody induced oligodendroglial morphological changes and increases in myelin basic protein and Klk6 expression. We also developed a novel enzyme-linked immunoabsorbent assay method for detecting activated KLK6 in human CSF. In human autopsy brain samples, expression of active KLK6 was detected in OLs using an antibody that specifically recognizes the protein's activated form. Taken together, our findings demonstrate that Klk6 secreted by OLs plays a critical role in the pathogenesis of EAE/MS and that it might serve as a potential therapeutic target for MS.
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PMID:Kallikrein 6 secreted by oligodendrocytes regulates the progression of experimental autoimmune encephalomyelitis. 2908 42