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.