Rasagiline protects against alpha-synuclein induced sensitivity to oxidative stress in dopaminergic cells.
Rasagiline is a propargylamine and irreversible monoamine oxidase (MAO) B inhibitor used for the treatment of Parkinson's disease (PD). It has demonstrated neuroprotective properties in laboratory studies. Current concepts of PD aetiopathogenesis include the role of alpha-synuclein, protein aggregation, free radical metabolism and mitochondrial dysfunction in contributing to cell death. We have used a combination of alpha-synuclein and free radical mediated toxicity in a dopaminergic cell line to provide a model of nigral toxicity in order to investigate the potential molecular mechanisms that mediate rasagiline protection. We demonstrate that rasagiline protects against cell death induced by the combination of free radicals generated by paraquat and either wild-type or A53T mutant alpha-synuclein over-expression. This protection was associated with a reduction in caspase 3 activation, a reduction in superoxide generation and a trend to ameliorate the fall in mitochondrial membrane potential. Rasagiline induced an increase in cellular glutathione levels. The results support a role for rasagiline in protecting dopaminergic cells against free radical mediated damage and apoptosis in the presence of alpha-synuclein over-expression. The data are of relevance to the interpretation of the potential mechanisms of action of rasagiline in explaining the results of disease modification trials in PD.
Chau
K Y
KY
Department of Clinical Neurosciences, UCL Institute of Neurology, London, United Kingdom.
Cooper
J M
JM
Schapira
A H V
AH
D053148:Caspase 3 / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004298:Dopamine / Q000502:physiology*; D004789:Enzyme Activation / Q000187:drug effects; D005609:Free Radicals / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D007189:Indans / Q000494:pharmacology*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008564:Membrane Potentials / Q000187:drug effects; D051336:Mitochondrial Membranes / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects*; D010269:Paraquat / Q000037:antagonists & inhibitors / Q000633:toxicity; D017382:Reactive Oxygen Species / Q000378:metabolism; D051844:alpha-Synuclein / Q000037:antagonists & inhibitors* / Q000633:toxicity*
D005609:Free Radicals; D007189:Indans; D018696:Neuroprotective Agents; D017382:Reactive Oxygen Species; D051844:alpha-Synuclein; C031967:rasagiline; D007770:L-Lactate Dehydrogenase; D053148:Caspase 3; D005978:Glutathione; D010269:Paraquat; D004298:Dopamine