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)

The signaling molecule Sonic hedgehog (Shh) is involved in several processes of central nervous system development. Recent reports indicate that Shh expression plays a role also in certain pathologic conditions in the adult brain, including multiple sclerosis and its animal model. However, the role of Shh signaling in immune-mediated demyelinating disease remains still uncertain. The aim of our study was to investigate the distribution pattern of Shh immunoreactivity (Shh-IR) during lesion evolution in myelin-oligodendrocyte-glycoprotein-induced experimental autoimmune encephalomyelitis (MOG-EAE), a model strongly mimicking multiple sclerosis. MOG-EAE was actively induced in DA rats. Histologic evaluation was performed with light and confocal microscopy on paraffin-embedded central nervous system sections from days 20 to 120 after active immunization. Shh-IR was present within the lesions of MOG-EAE during all stages of lesion evolution. The highest staining intensity for Shh was found in remyelinating lesions. In actively demyelinating, inactive demyelinated lesions, and in remyelinating lesions, Shh-IR was detected in macrophages, endothelium, and astrocytes. Shh-IR in axons was exclusively present in remyelinating lesions. Although the exact molecular mechanisms of the Shh-signaling pathway in experimental autoimmune encephalomyelitis are yet to be determined, our findings may imply a role of Shh signaling in facilitating remyelination.
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PMID:Differential expression of sonic hedgehog immunoreactivity during lesion evolution in autoimmune encephalomyelitis. 1589 98

Enhancing repair of myelin is an important but still elusive therapeutic goal in many neurological disorders. In multiple sclerosis, an inflammatory demyelinating disease, endogenous remyelination does occur but is frequently insufficient to restore function. Both parenchymal oligodendrocyte progenitor cells and endogenous adult neural stem cells resident within the subventricular zone are known sources of remyelinating cells. Here we characterize the contribution to remyelination of a subset of adult neural stem cells, identified by their expression of Gli1, a transcriptional effector of the sonic hedgehog pathway. We show that these cells are recruited from the subventricular zone to populate demyelinated lesions in the forebrain but never enter healthy, white matter tracts. Unexpectedly, recruitment of this pool of neural stem cells, and their differentiation into oligodendrocytes, is significantly enhanced by genetic or pharmacological inhibition of Gli1. Importantly, complete inhibition of canonical hedgehog signalling was ineffective, indicating that the role of Gli1 both in augmenting hedgehog signalling and in retarding myelination is specialized. Indeed, inhibition of Gli1 improves the functional outcome in a relapsing/remitting model of experimental autoimmune encephalomyelitis and is neuroprotective. Thus, endogenous neural stem cells can be mobilized for the repair of demyelinated lesions by inhibiting Gli1, identifying a new therapeutic avenue for the treatment of demyelinating disorders.
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PMID:Inhibition of Gli1 mobilizes endogenous neural stem cells for remyelination. 2648 Oct 96

Inflammation of the central nervous system (CNS) induces endothelial blood-brain barrier (BBB) opening as well as the formation of a tight junction barrier between reactive astrocytes at the Glia Limitans. We hypothesized that the CNS parenchyma may acquire protection from the reactive astrocytic Glia Limitans not only during neuroinflammation but also when BBB integrity is compromised in the resting state. Previous studies found that astrocyte-derived Sonic hedgehog (SHH) stabilizes the BBB during CNS inflammatory disease, while endothelial-derived desert hedgehog (DHH) is expressed at the BBB under resting conditions. Here, we investigated the effects of endothelial Dhh on the integrity of the BBB and Glia Limitans. We first characterized DHH expression within endothelial cells at the BBB, then demonstrated that DHH is down-regulated during experimental autoimmune encephalomyelitis (EAE). Using a mouse model in which endothelial Dhh is inducibly deleted, we found that endothelial Dhh both opens the BBB via the modulation of forkhead box O1 (FoxO1) transcriptional activity and induces a tight junctional barrier at the Glia Limitans. We confirmed the relevance of this glial barrier system in human multiple sclerosis active lesions. These results provide evidence for the novel concept of "chronic neuroinflammatory tolerance" in which BBB opening in the resting state is sufficient to stimulate a protective barrier at the Glia Limitans that limits the severity of subsequent neuroinflammatory disease. In summary, genetic disruption of the BBB generates endothelial signals that drive the formation under resting conditions of a secondary barrier at the Glia Limitans with protective effects against subsequent CNS inflammation. The concept of a reciprocally regulated CNS double barrier system has implications for treatment strategies in both the acute and chronic phases of multiple sclerosis pathophysiology.
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PMID:Blood-brain barrier genetic disruption leads to protective barrier formation at the Glia Limitans. 3325 45