The 1960s was a decade of breakthroughs for the management of the neuromotor degenerative condition, Parkinson’s Disease (PD), once known as the “Shaking Palsy.” In the 19th century, and until the middle twentieth, treatments for the reduction of tremors had been limited to acetylcholine inhibitors (anticholinergics), and by surgery to lesion the basal ganglia structures of the brain. But researchers in these years before the Second World War working to isolate and understand an amino acid in faba beans called dihydroxyphenylalamine would unknowingly change this. Levodopa, or simply “L-dopa,” was isolated as a chemical structure (1913) and shown to be biologically active as a metabolic precursor to such substances as dopamine and noradrenaline (1938).
Chemical structure of L-Dopa
In 1957, English researcher Kathleen Montagu provided a basic clue to the biological importance of dopamine and l-dopa when she cited the occurrence of dopamine in the brain; and Swedish scientist Arvid Carlsson confirmed dopamine as a neurotransmitter and modulator the following year. Carlsson developed a method to actually measure dopamine levels in brain tissues, particularly in those parts of the brain important for movement. He showed that a decrease in dopamine levels brought on symptoms in animals similar to those seen in Parkinson’s patients and this opened the door to possibly managing the disease if these levels could be increased or supplemented.
The tentative case in the 1950s for the linkage between dopamine levels and Parkinson’s became more substantial with back-to-back discoveries in 1960 and 1961. First, postmortem exams of Parkinson’s patients identified a positive dopamine deficiency in brain regions involved with movement control. Second, intravenous injections of levodopa in clinical trials showed dramatic success in restoring impaired motor function (akinesia) by replacing missing dopamine in patients. By 1966, clinical evidence for a levodopa-dopamine connection as a potential Parkinson’s therapy was overwhelming. Levodopa crossed the blood-brain barrier unlike dopamine itself. Moreover, it converted to dopamine in the central and peripheral nervous systems for systemic benefits. As a therapy, though, l-dopa remained elusive for the long-term management of Parkinson’s symptoms because of serious pulmonary and gastrointestinal side effects brought on by injected l-dopa.
Dr. George C. Cotzias, M.D.
In May 1967, Melvin Yahr and Margaret Hoehm published in the journal Neurology a system for describing the progression of Parkinson’s symptoms in something now known as the Hoehn & Yahr Scale. But treatment of the disease remained elusive and risky until Dr. George C. Cotzias at the Rockefeller Institute for Medical Research cracked the problem of L-dopa therapy. He used smaller doses than in previous studies, gave them orally and, under close observation, increased regimens on a bi-hourly basis until remission of PD symptoms occurred. Results of this large-scale study were published in 1968 in the New England Journal of Medicine. Double-blind studies in 1969 confirmed Cotzias results, and that year Cotzias won the Lasker-DeBakey Award for Clinical Medical Research. The FDA approved levodopa for treatment of PD in 1970.
Today, therapies involving stem cells, surgery, deep-brain stimulation, and physical therapy exist for Parkinson’s, but levodopa remains the “gold standard” of care; and has been enhanced by several so-called “dopamine agonists” developed in the 1960s era such as bromocriptine, apomorphine, and deprenyl which activate dopamine receptors. As the result of research in this period, the understanding of dopamine advanced markedly and has been demonstrated to participate in ADHD, schizophrenia, restless leg syndrome, and bipolar disorder.
In the way the 1960s was the era of Boeing Aircraft, the Boston Celtics, and Midcentury Modern architecture, these years were also key for Parkinson’s Disease neuroscience. The achievements of these years to determine the applications of L-Dopa to human health were immortalized in the 1990 movie Awakenings in which neurologist Oliver Sachs used large doses of L-Dopa with his patients with encephalitis lethargic.