title: Novel therapeutic approaches in multiple system atrophy.
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 α-synuclein-containing inclusions, particularly in the cytoplasm of oligodendrocytes (glial cytoplasmic inclusions, GCIs), which are associated with neurodegeneration. The mechanisms by which oligodendrocytic α-synuclein inclusions cause neuronal death in MSA are not completely understood. The MSA neurodegenerative process likely comprises cell-to-cell transmission of α-synuclein in a prion-like manner, α-synuclein 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 α-synuclein to oligodendroglia; rifampicin, lithium, and non-steroidal anti-inflammatory drugs, which inhibit α-synuclein 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 review.
authors.affiliation: Department of Neurology, Dysautonomia Center, New York University School of Medicine, 530 First Av, Suite 9Q, New York, NY, 10016, USA.
authors.forename: Jose-Alberto
authors.initials: JA
authors.lastname: Palma
authors.forename: Horacio
authors.initials: H
authors.lastname: Kaufmann
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D018450:Disease Progression; D006801:Humans; D051379:Mice; D019578:Multiple System Atrophy / Q000188:drug therapy* / Q000503:physiopathology*; D019636:Neurodegenerative Diseases / Q000188:drug therapy* / Q000503:physiopathology*; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D009836:Oligodendroglia / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051844:alpha-Synuclein / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D018696:Neuroprotective Agents; D051844:alpha-Synuclein