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.
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. It has been known since the 1950’s that levodopa (
prolongs the lives of patients with Parkinson’s disease [
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 [
Parkinson’s disease is caused by the destruction of dopaminergic neurons, especially in the midbrain. Animal models of Parkinson’s disease have shown that dopaminergic neurons undergo apoptosis or necrosis [
The major oxidation of dopamine occurs by MAO which produces oxygen radicals as part of its mechanism. These radicals attack DNA very rapidly [
Several mechanisms of oxygen radical formation in dopaminergic neurons are known. A minor mechanism is that dopamine may oxidize, nonenzymatically, forming oxygen radicals, dopaminequinones, dopamine semiquinones and neuromelanin [
Dopamine oxidation by MAO is a major factor in the progression of Parksinons’s disease. Dopamine autoxidation is clearly not the major mechanism involved the progression of Parkinson’s disease. Levodopa therapy increases brain dopamine levels, increases dopamine turnover and prolongs the lives of patients [14-16]. Levodopa greatly improves the quality of life and length of
life in Parkinson’s disease patients [
Several antioxidants, that protect lipids from oxygen radical damage, have been examined with no success. Vitamin E is a very potent inhibitor of lipid peroxidation and is not effective at slowing the progression of the disease [
Current therapy involves dopaminergic agonists, pramipexole andropinirole, as the first therapy in Parkinson’s disease or as adjuncts to levodopa [17-19]. There is preliminary evidence that these agents may be able to slow down disease progression [20-22]. However, studies must be done to see if dopamine agonists really extend the lives of patients. Despite putative neuroprotection in a five year study with ropinirole and pramipexole, the motor scores of patients were worse than levodopa treated patients [
Both pramipexole and ropinirole have toxicity problems in patients. They induce orthostatic hypotension and dizziness [
Dopaminergic neurons die through both necrotic and apoptotic mechanisms. Necrosis involves swelling and rupture of the nucleus, swelling and rupture of the cytoplasm, intranuclear vacuoles, loss of cytoplasmic organization, and occasionally mitochondrial swelling [29,30]. Apoptosis involves condensation of the nucleus, condensation of the cytoplasm, large cytoplasmic vacuoles, and mitochondrial shrinkage, leading to disintegration of the cell with the formation of apoptotic bodies [29-31].
Work with t-butylhydroperoxide, an oxidative stress inducing agent, has shown that the dose of oxidative stress determines whether the cells die predominantly from necrosis or apoptosis [29,30,32]. The presence of large amounts of reactive oxygen species causes predominantly necrosis. DNA is a primary target of oxygen radicals and fragments within minutes [30-32]. This activates poly(ADP-ribose) polymerase and other protective enzymes [30-32]. Normal cellular defense mechanisms, involving glutathione and other mechanisms, are overwhelmed [33-35]. The normal energy supply, involving ATP, NADH and NADPH, is exhausted [
Apoptosis involves a smaller dose of reactive oxygen species [29,30,32]. A small amount of DNA fragmentation occurs. Protective enzymes are activated, without the depletion of ATP, NADH and NADPH. DNA fragmentation may activate apoptotic programs that lead to delayed cell death. The apoptotic programs activated in Parkinson’s disease have been described [
Free dopamine, in nerve terminals, can oxidize and producequinones, semiquinones and neuromelanin [
A hallmark of Parkinson’s disease is low levels of dopamine in the striatum [
Inhibition of MAO B is a therapeutic mechanism used in Parkinson’s disease with selegiline. The inhibition of MAO B could decrease oxygen radical formation in dopaminergic neurons and could be neuroprotective. The DATATOP study and studies by the Norwegian-Danish Study Group and the Swedish Parkinson Study Group have shown that selegilinedelays the need for levodopa therapy and slows down disease progression [41-43]. However, selegiline can also causepostural hypotension, arrhythmias, hypertension and the serotonin syndrome [
complications due to the serotonin syndrome [
Aldehyde dehydrogenase is a family of related enzymes that oxidize exogenous and endogenous aldehydes. The brain contains fairly abundant amounts of aldehyde dehydrogenase [
A sulfhydryl and NAD+ are present inthe catalytic center of aldehyde dehydrogenase. The sulfhydryl is probably active as a thiolate anion (
The sulfhydryl binds aldehydes, which allows NAD+ to abstract hydrogen from the aldehyde forming a pyridinyl radical and a substrate radical [
bound ketone is formed, that hydrolyzes making the product acid.
Aldehyde dehydrogenase inhibitors could be considered for use in Parkinson’s disease. Aldehyde dehydrogenase inhibitors could slow down the progression of the disease, since they might inhibit oxygen radical formation. There is a major interaction of alcohol and aldehyde dehydrogenase inhibitors. Severe nausea and vomiting can result from this interaction and may seriously limit the use of aldehyde dehydrogenase inhibitors in Parkinson’s disease.
Tyrosine hydroxylase makes dopamine from tyrosine and is the rate limiting enzyme in the synthesis of dopamine [
Tyrosine hydroxylase performs both one and two electron reductions [
This involves electron donation from tetrahydrobiopterin 1 to ferric iron making 2, the radical cation [49,53]. This is the major mechanism of the enzyme.Oxygen interacts with the radical cationforming an unstable intermediate such as a peroxyl radical or radical hydroperoxide 3. In addition, oxygen can interact with the radical cation to produce superoxide. Otherresearch has also found oxygen radical generation from tyrosine hydroxylase [54, 55].
Levodopa should remain the mainstay of Parkinson’s disease therapy [
inhibit tyrosine hydroxylase anddecrease oxygen radical formation by the enzyme [
Levodopa is clearly toxic to neurons in culture [
Inhibitors of tyrosine hydroxylase, other than levodopa, should be examined in Parkinson’s disease. Patients on levodopa appear to exist for years with inhibited tyrosine hydroxylase. Other inhibitors might be useful in Parkinson’s disease. Tyrosine hydroxylase inhibitors could provide a new approach to the treatment of Parkinson’s disease.
Neuroprotection through protection of DNA in dopaminergic neurons is an approach to the treatment of Parkinson’s disease. Nicotinamide, a vitamin B3, has been shown to protect DNA in the midbrain and decrease cell death in a model of Parkinson’s disease [
Nicotinamide has been shown to decrease cell death that occurs through apoptotic or necrotic mechanisms [9, 30,57-60]. In animals treated with t-butylhydroperoxide, apoptosis decreased in the brains of animals treated with nicotinamide [
Up to 30% of elderly people are deficient in nicotinamide [
The toxicity of nicotinamide is mild. Nicotinamideis associated with none of thetoxicity of niacin. Nicotinamidehas been shown to produce vasodilation, induce several enzymes and inhibit the synthesis of other enzymes [
Many important mechanisms of oxygen radical formation exist in dopaminergic neurons. MAO makes oxygen radicalsandis important in Parkinson’s disease. MAO B inhibition is a widely used therapy in Parkinson’s disease, although the benefits may be mild. The formation of oxygen radicals by aldehyde dehydrogenase is not a current therapeutic target in Parkinson’s disease. Inhibition of aldehyde dehydrogenase can produce very unpleasant interactions with alcohol. Tyrosine hydroxylase induced oxygen radical formation is already a mainstay in Parkinson’s disease therapy with levodopa. Levodopa causes dopamine levels to increase in dopaminergic neurons, which can inhibit tyrosine hydroxylase through feed back inhibition. Nicotinamide protects neuronal DNA, is neuroprotective and should be explored as a means of decreasing the progression of Parkinson’s disease.