Abstract
Tyrosine hydroxylase, monoamine oxidase and aldehyde dehydrogenase all form oxygen radicals as part of their mechanisms of action. These oxygen radicals damage dopaminergic neurons in the substantianigra of the midbrain and cause them to die by a process of necrosis or apoptosis. Oxygen radicals quickly abstract hydrogen from DNA forming DNA radicals and causing DNA fragmentation, activation of DNA protective mechanisms, NAD depletion and cell death. Tyrosine hydroxylase is present in all dopaminergic neurons, is involved in the synthesis of dopamine and forms oxygen radicals in a redox mechanism involving its cofactor, tetrahydrobiopterin. Levodopa is used therapeutically in Parkinson’s disease patients since it is a precursor for dopamine, an inhibitor of tyrosine hydroxylase, and prolongs pa-tient’s lives. Monoamine oxidase converts dopamine into 3,4-dihydroxyphenylacetaldehyde and forms oxygen radi-cals.Aldehyde dehydrogenase oxidizes the aldehyde and forms oxygen radicals and 3,4-dihydroxyphenylacetic acid. The treatment of Parkinson’s disease should involveinhibitors of oxygen radical formation in dopaminergic neurons and neuroprotective agents that stimulate DNA repair and prevent cell death.
Highlights
Even though drug therapy in Parkinson’s diseaseis effective treatment for the symptoms of patients in the early stages of the disease [1,2], the disease progresses
Monoamine oxidase and aldehyde dehydrogenase all form oxygen radicals as part of their mechanisms of action. These oxygen radicals damage dopaminergic neurons in the substantianigra of the midbrain and cause them to die by a process of necrosis or apoptosis
Tyrosine hydroxylase is present in all dopaminergic neurons, is involved in the synthesis of dopamine and forms oxygen radicals in a redox mechanism involving its cofactor, tetrahydrobiopterin
Summary
Even though drug therapy in Parkinson’s diseaseis effective treatment for the symptoms of patients in the early stages of the disease [1,2], the disease progresses. Newdrug therapy in Parkinson’s disease should involveneuroprotective agents that protect the brain from the damaging effects of oxygen radicals and slow down the progression of the disease [1]. A minor mechanism is that dopamine may oxidize, nonenzymatically, forming oxygen radicals, dopaminequinones, dopamine semiquinones and neuromelanin [10] Another minor pathway involves MAO formation of dopaminesemiquinone radicals and similar metabolites of dopamine [11,12,13]. Despite putative neuroprotection in a five year study with ropinirole and pramipexole, the motor scores of patients were worse than levodopa treated patients [23] This result may indicate that levodopa slows disease progression whereas dopamine agonists do not. Longevity studies are required to see if dopamine agonists do slow down disease progression Both pramipexole and ropinirole have toxicity problems in patients. Cardiac toxicity from dopamine agonists may limit their use in Parkinson’s disease
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