Novel therapeutic approaches in multiple system at

Authors: JoseAlberto Palma Horacio Kaufmann

Publish Date: 2014/06/14

Volume: 25, Issue: 1, Pages: 37-45

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Abstract

Multiple system atrophy MSA is a sporadic adult onset relentlessly progressive neurodegenerative disease characterized by autonomic abnormalities associated with parkinsonism cerebellar dysfunction pyramidal signs or combinations thereof Treatments that can halt or reverse the progression of MSA have not yet been identified MSA is neuropathologically defined by the presence of αsynucleincontaining inclusions particularly in the cytoplasm of oligodendrocytes glial cytoplasmic inclusions GCIs which are associated with neurodegeneration The mechanisms by which oligodendrocytic αsynuclein inclusions cause neuronal death in MSA are not completely understood The MSA neurodegenerative process likely comprises celltocell transmission of αsynuclein in a prionlike manner αsynuclein aggregation increased oxidative stress abnormal expression of tubulin proteins decreased expression of neurotrophic factors excitotoxicity and microglial activation and neuroinflammation In an attempt to block each of these pathogenic mechanisms several pharmacologic approaches have been tried and shown to exert neuroprotective effects in transgenic mouse or cellular models of MSA These include sertraline paroxetine and lithium which hamper arrival of αsynuclein to oligodendroglia rifampicin lithium and nonsteroidal antiinflammatory drugs which inhibit αsynuclein aggregation in oligodendrocytes riluzole rasagiline fluoxetine and mesenchymal stem cells which exert neuroprotective actions and minocycline and intravenous immunoglobulins which reduce neuroinflammation and microglial activation These and other potential therapeutic strategies for MSA are summarized in this reviewHK receives research support from the National Institutes of Health NIH U54NS065736 The Autonomic Disorders Consortium U54NS065736 is a part of the NIH Rare Diseases Clinical Research Network RDCRN supported through collaboration between the NIH Office of Rare Diseases Research ORDR at the National Center for Advancing Translational Science NCATS and the NINDS The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH JAP receives support from The Dysautonomia Foundation Inc We acknowledge The Multiple System Atrophy MSA Coalition for supporting the 24th International Symposium on the Autonomic Nervous System where this paper was initially presented

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