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

Glial growth factor 2 (GGF2) is a neuronal signal that promotes the proliferation and survival of the oligodendrocyte, the myelinating cell of the central nervous system (CNS). The present study examined whether recombinant human GGF2 (rhGGF2) could effect clinical recovery and repair to damaged myelin in chronic relapsing experimental autoimmune encephalomyelitis (EAE) in the mouse, a major animal model for the human demyelinating disease, multiple sclerosis. Mice with EAE were treated with rhGGF2 during both the acute and relapsing phases. Clinically, GGF2 treatment delayed signs, decreased severity, and resulted in statistically significant reductions in relapse rate. rhGGF2-treated groups displayed CNS lesions with more remyelination than in controls. This correlated with increased mRNA expression of myelin basic protein exon 2, a marker for remyelination, and with an increase in the CNS of the regulatory cytokine, interleukin 10, at both the RNA and protein levels. Thus, a beneficial effect of a neurotrophic growth factor has been demonstrated on the clinical, pathologic, and molecular manifestations of autoimmune demyelination, an effect that was associated with increased expression of a T helper 2 cytokine. rhGGF2 treatment may represent a novel approach to the treatment of multiple sclerosis.
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PMID:The neuregulin, glial growth factor 2, diminishes autoimmune demyelination and enhances remyelination in a chronic relapsing model for multiple sclerosis. 970 7

Glial growth factor 2 (GGF2) is a neuronal signal that promotes the proliferation and survival of the oligodendrocyte, the myelinating cell of the central nervous system (CNS). This study has focused on recombinant human GGF2 (rhGGF2) and it's potential to affect clinical recovery and repair to damaged myelin in chronic relapsing experimental autoimmune encephalomyelitis (EAE) in the mouse, a major animal model for the human demyelinating disease, multiple sclerosis (MS). Mice with EAE were treated with rhGGF2 during both the acute and relapsing phases, and GGF2 treatment led to delayed signs, decreased severity and resulted in statistically significant reductions in relapse rate. Further, rhGGF2-treated groups displayed CNS lesions with more remyelination than in controls. This correlated with increased expression of myelin basic protein exon 2, a marker for remyelination, and with an increase of the regulatory cytokine, IL-10. Thus, a beneficial effect of a neurotrophic growth factor has been demonstrated upon the clinical, pathologic and molecular manifestations of autoimmune demyelination, an effect that was associated with increased expression of a Th2 cytokine. rhGGF2 treatment may represent a novel approach to the treatment of MS (Cannella et al., 1998).
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PMID:Neuregulin in neuron/glial interactions in the central nervous system. GGF2 diminishes autoimmune demyelination, promotes oligodendrocyte progenitor expansion, and enhances remyelination. 1063 37

Glial growth factor-2 (GGF-2) is a neuronally derived isoform of neuregulin shown in vitro to promote proliferation and survival of oligodendrocytes, the myelinating cells of the CNS. Enhanced remyelination has been demonstrated in vivo following systemic delivery of human recombinant GGF-2 (rhGGF-2) in experimental autoimmune encephalomyelitis (EAE). However, it is uncertain whether this is the result of direct effects of rhGGF-2 on cells of the oligodendrocyte lineage or due to modulation of the immune or inflammatory response. If this enhanced remyelination was due to direct effects of rhGGF-2 on cells of the oligodendrocyte lineage then one would expect rhGGF-2 to induce a similar proremyelinating response in nonimmune, gliotoxin models of demyelination. Using a gliotoxin model of demyelination we were therefore able to ascertain the in vivo effect of rhGGF-2 following local CNS delivery in a model that is not confounded by the concurrent presence of an immune-mediated process. No significant alteration in the rate or character of remyelination was evident following local delivery as compared to controls, and indeed nor following systemic delivery in the gliotoxin model. The results of this study therefore indicate that both direct infusion and systemic delivery of rhGGF-2 do not alter remyelination in a nonimmune, gliotoxin model of demyelination. This suggests that the proremyelinating effects of systemically delivered rhGGF-2 in EAE are unlikely to be due to direct effects on the oligodendrocyte lineage, but may be mediated by rhGGF-2 inducing an environment more favourable to remyelination, possibly through modulation of the immune response.
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PMID:Increasing local levels of neuregulin (glial growth factor-2) by direct infusion into areas of demyelination does not alter remyelination in the rat CNS. 1462 86

Soluble factors that promote survival and differentiation of glia and neurons during development are likely to play key roles in neurodegeneration and demyelinating diseases such as multiple sclerosis (MS) and have the potential to be important therapeutic targets. We examined the effect of TrkB signaling and the expression patterns of neurotrophic and gliotrophic factors in the mouse brain in MOG-induced experimental allergic encephalomyelitis (EAE). With induction of mild disease, TrkB heterozygous mice were more severely affected compared to their wild type littermates. However, with more potent disease induction, TrkB heterozygotes fared similar to their wild type littermates, suggesting complex modulatory roles for TrkB signaling. One possible explanation for this difference is that the expression patterns of neurotrophic factors correlate with disease severity in individual mice with mild disease, but not in more severe disease. With the less potent induction in C57BL/6 mice, we found that BDNF was consistently increased at EAE onset, while the soluble gliotrophic factor neuregulin (NRG1) was increased only in the chronic phase of the disease. Treatment of these animals with glatiramer acetate (GA) to decrease disease severity resulted in lower levels of both BDNF and NRG1 expression in some mice at 35days after immunization compared to those in untreated EAE mice, but had no direct effect on these factors in the absence of EAE. Our results suggest a complex interplay between neurotrophic and gliotrophic factors in EAE that is dependent on disease stage and severity. While signaling by BDNF through TrkB is protective in mild disease, this effect was not seen in more severe disease. The late induction of NRG1 in the chronic stage of disease could also worsen disease severity through its known ability to activate microglial, inflammatory pathways. While complex, these studies begin to define underlying axoglial trophic activities that are likely involved in both disease pathogenesis and repair.
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PMID:Complexity of trophic factor signaling in experimental autoimmune encephalomyelitis: differential expression of neurotrophic and gliotrophic factors. 2376 72

Neuregulin1 (NRG1) is a differentiation factor that regulates glial development, survival, synaptogenesis, axoglial interactions, and microglial activation. We previously reported that a targeted NRG1 antagonist (HBD-S-H4) given intrathecally, reduces inflammatory microglial activation in a spinal cord pain model and a neurodegenerative disease mouse model in vivo, suggesting that it may have effects in neuroninflammatory and neuronal disorders. We hypothesized that expression of HBD-S-H4 in the central nervous system (CNS) could reduce disease severity in experimental autoimmune encephalomyelitis (EAE), a widely used animal model for multiple sclerosis (MS). In the present study, we generated tetO-HBD-S-H4, a single transgenic (Tg) mouse line in, which the fusion protein in expressed in the brain, resulting in reduction of disease severity in both male and female mice when compared to sex- and age-matched wild type littermates. We also generated GFAP-tTA:tetO-HBD-S-H4 double Tg mice, which express this fusion protein in the brain and the spinal cord, they displayed sex differences in the reduction of disease severity. In healthy mice, expression of HBD-S-H4 in the CNS does not result in any significant neurological or other overt phenotypes. In myelin oligodendrocyte glycoprotein (MOG)-induced EAE, female double Tg mice show delayed disease onset and reduced disease severity compared to male double Tg as well as wild type littermates. In male double Tg mice, the levels of HBD-S-H4 gene expression negatively correlates with disease severity and increased microglia associated genes' expression. In conclusion, expression of neuregulin antagonist in the brain and spinal cord protects females but not males, suggesting a complex interplay between NRG1 and sex difference in EAE that may be associated with microglia-mediated inflammation. This study provides important information for understanding the heterogeneity of disease pathology and the therapeutic potential of targeting microglial activation in male and female MS patients.
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PMID:Neuregulin1 modulation of experimental autoimmune encephalomyelitis (EAE). 2953 47