On the history of levodopa

We should probably start in 1884 when a dopaminergic agonist improved the abnormal choreiform movements of a patient with Sydenham’s chorea—a disorder wholly unrelated to Parkinson Disease, or PD. Almost 70 years later, in 1950, the use of dopaminergic precursor was successfully attempted by Schwab and colleagues.

However, since the time when James Parkinson described his 6 original cases in 1817, patients received very little physical or pharmacotherapy. A number of patients were treated with the herbal alkaloid, atropa belladonna, otherwise known as deadly nightshade, whose anticholinergic effects were on occasion safely harnessed by apothecaries like Parkinson to manage the symptoms of his patient’s “shaking palsy.”

Because of the toxic side effects from belladonna in patients with PD, other therapies were explored, but none quite as popular as neurosurgery (below). The first surgical techniques were pioneered in 1909 when Sir Victor Horsley, one of the designers of the original stereotactic apparatus, resected a woman’s precentral gyrus to relieve her hemiathetosis. (You may recall that the precentral gyrus serves as the primary motor cortex.) As would be expected, many of these and other related procedures cured many patients of their tremor by paralyzing the affected extremity.

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Eventually, cryopallidectomy, or surgical ablation of the globus pallidus using extreme cold, became a standard of care, and this is what led us to the present day, 1960s dopamine hypothesis. Anticholinergics like belladonna have survived into the present day Parkinsonian pharmacopeia, but they are more frequently used as adjuncts for dystonia in younger populations. For more information on the selective utility of medications for PD, you should check out our episode by Dr. Coughlin which came out only a few weeks ago.

At this point in the show, let us welcome our guest to the stage. Queue levodopa. In 1957, in perhaps

Levodopa.

Levodopa.

the most historic discovery in movement disorders, Arvid Carlsson successfully alleviated Parkinsonian symptoms of animals with pharmacologically-induced Parkinsonism using levodopa. Publication of these results would eventually earn him the Nobel Prize half a century later, in fashionable delay as the Nobel prize committee is wont to do.

It was in this shadow that the landmark trial by George C. Cotzias and colleagues was published, and all doubts of the dopamine hypothesis were silenced. But many historians have argued that Cotzias stumbled upon this groundbreaking discovery. For more information on what happened then and in the years to follow, check out this week’s episode:

 

[Jim Siegler]


REFERENCES

Parkinson J. An essay on the shaking palsy. 1817. J Neuropsychiatry Clin Neurosci. 2002;14:223-36; discussion 222.

Glatstein M, Alabdulrazzaq F and Scolnik D. Belladonna Alkaloid Intoxication: The 10-Year Experience of a Large Tertiary Care Pediatric Hospital. Am J Ther. 2016;23:e74-7.

Koranyi EK. A preamble on parkinsonism. J Psychiatry Neurosci. 1999;24:296-9.

Bucy P and Case T. Tremor: Physiologic mechanism and abolition by surgical means. Arch Neurol Psych. 1939;41:721-746.

Walter BL, Abosch A and Vitek JL. From Neuroscience to Neurology: Molecular Medicine, and the Therapeutic Transformation of Neurology 2004.

Hornykiewicz O. A brief history of levodopa. Journal of neurology. 2010;257:S249-52.

Tolosa E, Marti MJ, Valldeoriola F and Molinuevo JL. History of levodopa and dopamine agonists in Parkinson’s disease treatment. Neurology. 1998;50:S2-10; discussion S44-8.

Birkmayer W and Hornykiewicz O. [The L-3,4-dioxyphenylalanine (DOPA)-effect in Parkinson-akinesia]. Wien Klin Wochenschr. 1961;73:787-8.

Cotzias GC, Van Woert MH and Schiffer LM. Aromatic amino acids and modification of parkinsonism. The New England journal of medicine. 1967;276:374-9.

Willis AW, Schootman M, Kung N, Wang XY, Perlmutter JS and Racette BA. Disparities in deep brain stimulation surgery among insured elders with Parkinson disease. Neurology. 2014;82:163-71.

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