Oleh Hornykiewicz (1926-2020)

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This week it was announced that Oleh Hornykiewicz had passed away.

I appreciate that most readers will not know who he is, but understand that his contribution to Parkinson’s research was important.

Not only was he instrumental in the discovery that dopamine is significantly reduced in the Parkinsonian brain, but he also demonstrated that levodopa treatment can help restore function.

In today’s post, we remember Oleh Hornykiewicz.

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It was sad to hear of the passing away of Oleh Hornykiewicz this week.

Most readers will have little clue as to who he was, but he played a very important role in the development of the Parkinson’s treatment we know of as levodopa therapy.

Very early in the 20th century, a chemical called dopamine was discovered, but no one really knew anything about it until a young Swedish research named Arvid Carlsson started to play with it.

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Prof Arvid Carlsson. Source: Alchetron

In 1957, Carlsson discovered that when he injected a drug called reserpine into the brains of rabbits, the animals exhibited limited ability to move. He found that reserpine depleted levels of dopamine in the brains of the rabbits. He also discovered that by injecting the dopamine precursor – levodopa (more on this below) – into those same animals, he was able to rescue their motor ability. Importantly, he found that the precursor (called 5-hydroxytryptophan) to another chemical called serotonin, it was not capable of reversing the reduction in motor ability, indicating that the effect was specific to levodopa and dopamine.

He published this amazing result in the prestigeous scientific journal ‘Nature’:

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Title: 3,4-Dihydroxyphenylalanine and 5-hydroxytryptophan as reserpine antagonists.
Authors: Carlsson A, Lindqvist M, Magnusson T.
Journal: Nature. 1957 Nov 30;180(4596):1200. No abstract available.
PMID: 13483658       (the article on the Nature website – access required)

This was a fantastic discovery.

But what to do with it?

And that is where an Austrian researcher named Oleh Hornykiewicz becomes part of the story.

Born 17 November (1926) in Sykhiv near Lviv in East Galicia (which initially belonged to Poland but is now part of Ukraine), Oleh attended the Sperlgymnasium in Vienna, before studying medicine at the University of Vienna. In 1951, he graduated as a doctor of general medicine and immediately jumped into research via an unpaid research assistant position at the University’s Pharmacology Institute.

In 1956, he moved to Oxford to join Hermann Blaschko’s biochemistry lab and began to research a collection of chemicals called catecholamines. Catecholamine are neurotransmitters – chemicals that pass messages between neurons. They includes noradrenaline, adrenaline, and dopamine (which Carlsson was about to show was a neurotransmitter).

Blaschko (left) & Hornykiewicz. Source: Wiley

Blaschko apparently asked Hornykiewicz to explore the possibility that dopamine was having its own physiological role in the body. And this started Oleh on an amazing path of research. When he returned to Austria in 1958, Hornykiewicz took a university assistant postition in the Pharmacology Institute of the University of Vienna, where he continued to investigate dopamine. In particular, Oleh started measuring levels of dopamine in samples of postmortem human brains.

In January 1959, two researchers in Arvid Carlsson’s laboratory, named Bertler and Rosengren (and incidentally at the same time, Isamu Sano & colleagues in Japan) published their research showing that in the brain of both dogs and humans, the bulk of the dopamine could be found in an area of the brain called the striatum.

In his own studies, Hornykiewicz also found very high levels of dopamine in the striatum of normal postmortem adult brains, but (and here was the first big discovery) in six postmortem cases of Parkinson’s he found a marked and consistent reduction (approx. 10-fold) in dopamine levels.

He published this result in this report:

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Title: Distribution of noradrenaline and dopamine (3-hydroxytyramine) in the human brain and their behavior in diseases of the extrapyramidal system
Authors: Ehringer H, Hornykiewicz O.
Journal: Parkinsonism Relat Disord. 1998 Aug;4(2):53-7. No abstract available.
PMID: 18591088

But critically, Hornykiewicz did not stop there.

In November 1960, he approached Walther Birkmayer, a neurologist at the largest municipal home for the aged in Vienna, and together they began some clinical trials of levodopa in people with Parkinson’s.

Hornykiewicz & Birkmayer (right). Source: Wiley

You will remember from above that this is the amino acid that Arvid Carlsson was injecting into rabbits after destroying their dopamine neurons, and this treatment made the animals more mobile. Levodopa is the precursor to dopamine and in the brain it is quickly converted by an enzyme called DOPA decarboxylase.  4INJ4aV

The chemical conversion of L-DOPA to dopamine. Source: Nootrobox

Oleh figured if dopamine is significantly reduced in the brains of people with Parkinson’s, then injecting them with levodopa may help to increase dopamine levels in the brain. DOPA decarboxylase is a widely produced enzyme in the brain, so even in the situation of reduced numbers of dopamine neurons, high levels of dopamine can be produced if levodopa is present.

In July 1961, Birkmayer injected 50 to 150 mg in saline intravenously into 20 volunteers with Parkinson’s, and the effect was spectacular. In their report, Birkmayer and Hornykiewicz wrote this regarding the results:

“The effect of a single intravenous injection of l-dopa was, in short, a complete abolition or substantial relief of akinesia. Bedridden patients who were unable to sit up, patients who could not stand up when seated, and patients who when standing could not start walking performed after l-dopa all of these activities with ease. They walked around with normal associated movements, and they could even run and jump. The voiceless, aphonic speech, blurred by palilalia and unclear articulation, became forceful and clear as in a normal person. For short periods of time the people were able to perform motor activities, which could not be prompted to any comparable degree by any other known drug”

Despite their initial excitement, Birkmayer and Hornykiewicz found that the response to levodopa was very limited in its duration. In addition, subsequent trials by others were not able to achieve similar results, with many failing to see any benefit at all (mixed results in clinical trials is not a recent phenomenon!).

And that was when George Cotzias stepped into the picture.

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Dr George Cotzias… and uh, yes he is holding a brain. Source: New Scientist

Dr George Cotzias was a physician working in New York who became very interested in the use of levodopa for Parkinson’s. And he discovered that by starting with very small doses of levodopa, given orally every two hours and increasing the dose gradually he was able to stabilise patients on large enough doses to cause a dramatic changes in their symptoms. His studies led ultimately to the US Food and Drug Administration (FDA) approving the use of levodopa for use in PD in 1970. Cotzias and his colleagues were also the first to describe levodopa–induced dyskinesias.

The medical history books on Parkinson’s will remember all of these gentleman for their contributions, which have altered how Parkinson’s has been treated in the last half century.

Arvid Carlsson was awarded a Nobel prize in 2000 for his initial discovery that dopamine was active (Cick here to read more about this). But there were many that thought Oleh Hornykiewicz should have shared that accolade with him. Following Arvid Carlsson’s Nobel prize in 2000, an open letter was sent to the Nobel Prize Committee in 2001 – signed by 230 scientists – registering their regret that Hornykiewicz had been overlooked for the prize considering his contributions.

Despite this oversight, Hornykiewicz was awarded many other prizes for his research during a very long career (he continued to work in his office nearly every day until he was well into his 90s).

An amazing contribution – a sad loss.

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Prof Oleh Hornykiewicz. Source: Kurienwissenschaftundkunst

 

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