Four individuals stand out as pioneers of the early work that led to
levodopa becoming a revolutionary new treatment for
Parkinson's disease: Arvid Carlsson, Oleh Hornykiewicz, George C. Cotzias, and Melvin D. Yahr. All four were MDs. The first three had extra training in pharmacology, and in fact did their research in pharmacology. The fourth was a clinical neurologist, the only one in this group with those credentials. The story starts with Carlsson, who became interested in studying the mechanism of
reserpine's
sedative effect, now recognized as a drug-induced parkinsonian state. A key experiment in 1957 showed that
levodopa (
l-dopa) could alleviate the immobility induced by
reserpine in animals. Carlsson then showed that
reserpine depleted brain
dopamine, and that
l-dopa restored it. Carlsson developed a sensitive fluorescent technique to measure
dopamine levels, and his laboratory also showed the distribution of
dopamine in animal brain to be highest in the striatum. Within a year, Carlsson postulated that
dopamine appears to play a role in motor function. His proposal that
dopamine serves as a
neurotransmitter in brain was met with much skepticism, but he persisted and continued to study brain
dopamine, eventually leading to being awarded the Nobel Prize in Medicine in 2000. Hornykiewicz also went into pharmacology research after graduating from medical school. Fortuitously, his assigned first project was on the blood pressure effects of
dopamine, recognized as a precursor of
norepinephrine. When he completed his postdoctoral studies, Carlsson's work on the reserpinized animal and on the regional distribution of brain
dopamine was published. This inspired Hornykiewicz to determine
dopamine levels in patients with
Parkinson's disease. He obtained postmortem material, and his 1960 paper showed a marked depletion of
dopamine in the striatum in this disorder. He went on in subsequent papers to correlate severity of parkinsonian features with the amount of striatal
dopamine depletion. In the meantime, after his discovery of low
dopamine in brains of patients with
Parkinson's disease, Hornykiewicz persuaded Walther Birkmayer to inject
l-dopa into patients. They reported success and continued this treatment, usually combining it with the use of a
monoamine oxidase inhibitor. However, the response was limited in duration, and subsequent trials by others were not achieving similar success, and many failed to find any benefit. The fulfilment of the
l-dopa story stemmed from the hypothesis held by Cotzias that
Parkinson's disease was caused by loss of brain
neuromelanin in the substantia nigra. Although Cotzias's research had been in pharmacology, he also headed a clinical pharmacology research group at a federal laboratory on Long Island, New York, USA. He decided to try to restore this pigment in patients, not animals, and one of the three drugs he tried was d,
l-dopa. As reported in his 1967 article, d,
l-dopa proved to be dramatically successful in reversing the symptoms, but at extremely high dosages and with considerable hematologic adverse effects. Cotzias immediately tested
l-dopa and found the same benefit with half the dosage and without the hematologic problems. Yahr was a clinical neurologist who had been treating patients with PD with available
therapy and also headed a federally financed research group investigating the disorder. Always on the lookout for potential new treatments, he was initially skeptical about
l-dopa when studies with low doses were being reported. Seeing videos of patients presented by Cotzias, however, he realized that the results needed confirmation through a double-blind controlled clinical trial. He proceeded to develop and execute such a trial with
l-dopa, duplicating Cotzias's success. Both Cotzias and Yahr had encountered motor fluctuations and
dyskinesias, but the amelioration of
bradykinesia, rigidity, and
tremor was so pronounced that these adverse effects did not prevent regulatory approval of
l-dopa, and almost 50 years later
l-dopa remains the most effective pharmacologic agent for treating
Parkinson's disease. This article relates the personal stories of these four pioneers and how they achieved their success.