Given this pathology, a logical approach to treating Parkinson's disease would be to try to restore the levels of dopamine in the CNS. It was well known that dopamine does not cross the blood-brain barrier because of its positive charge. However, zwitterionic amino acids had the advantage of broadly specific transport systems to carry them across this barrier into the brain. Based on this, a top candidate for increasing dopamine levels in the CNS would be its immediate precursor, L-dihydroxyphenylala-nine or L-dopa. Not only could L-dopa be transported across the blood-brain barrier, it also had the advantage of by-passing the rate limiting step in the synthesis of catecholamines, tyrosine hydroxylase. This, in turn, provided two advantages. First, it avoided the slowest step in the synthetic process. In addition, tyrosine hydroxylase had been shown to be present only in catecholamine-containing neurons in the CNS, the very neurons that were disappearing in Parkinson's disease. Second, aromatic amino acid decarboxylase (dopa decarboxylase), the enzyme converting L-dopa to dopamine, although shown to be primarily in dopamine neurons in the corpus stria-tum, was also clearly found in non-dopamine cells (i.e., serotonin and norepinephrine terminals).19,49 As a result, the loss of this enzyme in Parkinson's disease was not as dramatic as the loss of tyrosine hydroxylase,50 and so use of dopa decarboxylase as a critical enzymatic step in treatment would be expected to be more successful than going through tyrosine hydroxylase.
Several groups tried administering large doses of L-dopa to Parkinson's patients and found promising results, particularly in combating akinesia.51-53 There were, however, significant side effects associated with this therapy, and they threatened to severely limit its usefulness. Several significant improvements were made in an extensive study by Cotzias and colleagues.54 In their own initial studies, they had used racemic dopa and had encountered serious side effects.53 In the later study,54 they used only L-dopa, as had others previously, and found that the use of the stereoisomer instead of the racemic mixture reduced the incidence of side effects greatly, including avoiding some of the most problematic, such as reversible granulocytopenia. They found that slowly increasing the dose also reduced the incidence of side effects. Perhaps most important, they introduced the use of a peripheral dopa decarboxylase inhibitor. They reasoned that many of the side effects that had been encountered could be explained by the conversion of L-dopa to dopamine and norepinephrine in the periphery. If this peripheral conversion could be reduced or stopped, the side effects should be reduced, and more L-dopa would be available for transport into the CNS. Animal studies had provided support for this notion.55 56 Using this approach, Cotzias and colleagues were very successful in reducing side effects and in allowing a reduction in the dosage of L-dopa necessary to produce beneficial effects in Parkinson's patients.54 These early studies in humans introducing L-dopa therapy as a means of partially restoring central dopamine levels, and hence countering the symptoms of Parkinson's disease, initiated what is currently the most common therapeutic approach to treating Parkinson's disease.
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