title: High dose levodopa therapy is not toxic in multiple system atrophy: experimental evidence.
abstract: Levodopa is generally regarded the first choice therapy for parkinsonism associated with multiple system atrophy (MSA-P). However, MSA-P patients often show a poor or unsustained levodopa response which inflicts high dose therapy. This is generally attributed to progressive striatal degeneration with loss of dopamine receptors. Experimental evidence suggests that dopaminergic stimulation may accelerate the striatal disease process in MSA, possibly by pro-oxidative mechanisms. Intact nigrostriatal dopamine release augments striatal lesion size in the unilateral nigral and striatal double lesion rat model of MSA-P. Further, neuronal vulnerability to exogenous oxidative stress is increased in a transgenic MSA mouse model with oligodendroglial alpha-synuclein inclusions. The aim of the present study was to analyze whether high dose levodopa delivery in the transgenic MSA model is associated with neurotoxicity exacerbated by the presence of oligodendroglial alpha-synuclein inclusion pathology. Control and transgenic MSA mice underwent pulsatile treatment with either vehicle, low or high dose levodopa for a period of 1 month. Behavioral and neuropathological indices failed to show evidence for neurotoxic effects of high-dose levodopa in this alpha-synuclein transgenic MSA model. These findings support the idea that high dose levodopa therapy in MSA is not detrimental to the underlying neuropathological process.
authors.affiliation: Clinical Neurobiology Unit, Department of Neurology, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: Nadia
authors.initials: N
authors.lastname: Stefanova
authors.forename: Martin
authors.initials: M
authors.lastname: Köllensperger
authors.forename: Monika
authors.initials: M
authors.lastname: Hainzer
authors.forename: Angela
authors.initials: A
authors.lastname: Cenci
authors.forename: Werner
authors.initials: W
authors.lastname: Poewe
authors.forename: Gregor Karl
authors.initials: GK
authors.lastname: Wenning
mesh_terms: D000704:Analysis of Variance; D000820:Animal Diseases; D000818:Animals; D000978:Antiparkinson Agents / Q000627:therapeutic use*; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D007980:Levodopa / Q000627:therapeutic use*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D019578:Multiple System Atrophy / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology; D009419:Nerve Tissue Proteins / Q000378:metabolism; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism
chemical_list: D000978:Antiparkinson Agents; D009419:Nerve Tissue Proteins; D051844:alpha-Synuclein; D007980:Levodopa