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)

Progressive multiple sclerosis is associated with metabolic failure of the axon and excitotoxicity that leads to chronic neurodegeneration. Global sodium-channel blockade causes side effects that can limit its use for neuroprotection in multiple sclerosis. Through selective targeting of drugs to lesions we aimed to improve the potential therapeutic window for treatment. This was assessed in the relapsing-progressive experimental autoimmune encephalomyelitis ABH mouse model of multiple sclerosis using conventional sodium channel blockers and a novel central nervous system-excluded sodium channel blocker (CFM6104) that was synthesized with properties that selectively target the inflammatory penumbra in experimental autoimmune encephalomyelitis lesions. Carbamazepine and oxcarbazepine were not immunosuppressive in lymphocyte-driven autoimmunity, but slowed the accumulation of disability in experimental autoimmune encephalomyelitis when administered during periods of the inflammatory penumbra after active lesion formation, and was shown to limit the development of neurodegeneration during optic neuritis in myelin-specific T cell receptor transgenic mice. CFM6104 was shown to be a state-selective, sodium channel blocker and a fluorescent p-glycoprotein substrate that was traceable. This compound was >90% excluded from the central nervous system in normal mice, but entered the central nervous system during the inflammatory phase in experimental autoimmune encephalomyelitis mice. This occurs after the focal and selective downregulation of endothelial p-glycoprotein at the blood-brain barrier that occurs in both experimental autoimmune encephalomyelitis and multiple sclerosis lesions. CFM6104 significantly slowed down the accumulation of disability and nerve loss in experimental autoimmune encephalomyelitis. Therapeutic-targeting of drugs to lesions may reduce the potential side effect profile of neuroprotective agents that can influence neurotransmission. This class of agents inhibit microglial activity and neural sodium loading, which are both thought to contribute to progressive neurodegeneration in multiple sclerosis and possibly other neurodegenerative diseases.
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PMID:Lesional-targeting of neuroprotection to the inflammatory penumbra in experimental multiple sclerosis. 2428 15

Progressive multiple sclerosis (PMS) is a devastating disorder sustained by neuroimmune interactions still wait to be identified. Recently, immune-independent, neural bioenergetic derangements have been hypothesized as causative of neurodegeneration in PMS patients. To gather information on the immune and neurodegenerative components during PMS, in the present study we investigated the molecular and cellular events occurring in a Non-obese diabetic (NOD) mouse model of experimental autoimmune encephalomyelitis (EAE). In these mice, we also evaluated the effects of clinically-relevant immunosuppressive (dexamethasone) or bioenergetic drugs (bezafibrate and biotin) on functional, immune and neuropathological parameters. We found that immunized NOD mice progressively accumulated disability and severe neurodegeneration in the spinal cord. Unexpectedly, although CD4 and CD8 lymphocytes but not B or NK cells infiltrate the spinal cord linearly with time, their suppression by different dexamethasone treatment schedules did not affect disease progression. Also, the spreading of the autoimmune response towards additional immunogenic myelin antigen occurred neither in the periphery nor in the CNS of EAE mice. Conversely, we found that altered mitochondrial morphology, reduced contents of mtDNA and decreased transcript levels for respiratory complex subunits occurred at early disease stages and preceded axonal degeneration within spinal cord columns. However, the mitochondria boosting drugs, bezafibrate and biotin, were unable to reduce disability progression. Data suggest that EAE NOD mice recapitulate some features of PMS. Also, by showing that bezafibrate or biotin do not affect progression in NOD mice, our study suggests that this model can be harnessed to anticipate experimental information of relevance to innovative treatments of PMS.
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PMID:Neuroimmunological characterization of a mouse model of primary progressive experimental autoimmune encephalomyelitis and effects of immunosuppressive or neuroprotective strategies on disease evolution. 3153 28