Thomas A. Ban
Neuropsychopharmacology in Historical Perspective.
Education in the field in the Post-Psychopharmacology Era
Joseph Knoll: The discoveryof monoamine oxidase (MAO) enzymes
Neuropsychopharmacology in Historical Perspective.
Hector Warnes’ comment
This is a complex and profound paper on the monoamine-oxidase (MAO) enzymes which should really be reviewed by an expert pharmacologist and neuro-biochemist. Professor Knoll (1925-2018) writes about Herman K. Felix Blaschko <s>(from Berlin and London)</s> who preceded him and was a source of inspiration for his work on the MAO system. It seems that with amazing transparency Professor Knoll wanted to give credit where it was due.
Professor Blaschko's presented accounts of his research activities in two publications, “My Path to Pharmacology” (1980) and, more specifically to MAO, “The natural history of amine oxidase” (1974).
At some point in time research activities of the two great men overlapped, with most of the research on the MAO-A carried out by Blaschko and that on MAO-B by Knoll. The latter published a paper on his contributions to these discoveries titled “Memories of my 45 years in research” (1994); a most interesting interview was conducted by Professor Thomas Ban in 2002 and appeared on the INHN website (Ban 2018).
Deprenyl (Selegiline) is a MAO-B inhibitor which was first synthesized by Professor Knoll at his Laboratory of Semmelweis University in Budapest (Knoll and Magyar 1972). Deprenyl induces irreversible inhibition of MAO-B thus increasing the availability of dopamine in the substancia nigra where the neurons start dying out (apoptosis) in Parkinson’s disease. In 1989 Knoll also discovered the nootropic anti-aging effect of Deprenyl which he called "mesencephalic enhancer regulation" (Knoll 1998).
Inhibition of MAO-A and MAO-B in the brain yields higher concentrations of serotonin, norepinephrine and dopamine in the synapse. Blaschko pointed out that tyrosine converts into levodopa, levodopa into dopamine which in turns converts into noradrenaline and finally to adrenaline. He further pointed out that MAO-A is primarily responsible for the oxidative deamination of the mono-amine serotonin, melatonin, norepinephrine and epinephrine (adrenaline). Put into a time perspective, Blaschko and his co-workers discovered the generalized amine oxidase properties in 1937 while Professor Knoll was courting death in a Nazi concentration camp where all his family perished.
On this side of the Atlantic, in 1965 J.J. Schildraut published “The catecholamine hypothesis of affective disorders: a review of supporting evidence” which, 50 years later, was replaced by other theories, including the glutamate hypothesis of depression (Sanacora, Treccani and Popoli 2012).
The era of antidepressants really started accidentally in 1952 when Kline, Loomer and Saunders used Iproniazid (isonicotinyl hydrazine) in patients suffering from tuberculosis and it was observed to have mood elevating properties. Nathan Kline called this compound a "psychic energizer." A review of this break-through was documented in a 2009 paper by López-Muñoz and Alamo.
In spite of a 70% improvement rate in Nathan Kline's clinical trials Iproniazid (identified by Blaschko in 1937) was withdrawn from the market because of hepato- and nephrotoxicity. Other MAO inhibitors were used in atypical depression refractory to second or third generation antidepressants. Barry Blackwell published “Hypertensive crises due to MAOI” in 1963 in which he reported that the so-called "cheese effect" caused severe hypertensive crises due to interaction with sympathomimetic drugs and tyramine containing foods.
Less toxicity was achieved with the transdermal MAO (Selegiline) which delivers directly into the circulation. Due to the high percentage of treatment resistant depressions which usually are associated with co-morbidity and heavy genetic load, the optimal drug for these cases has not been found. Drug resistant severe depression as well is associated with aging and many other variables including those investigated by Professor Knoll, a pioneer on this field of research.
Ban TA. In Memory of Joseph Knoll (1925 – 2018). inhn.org.biographies. November 8, 2018.
Blackwell B. Hypertensive crises due to MAOI. The Lancet 1963; ii:849-51.
Blaschko HKF. My Path to Pharmacology. In: Annual Review of Pharmacology and Toxicology. 1980; 20:1-15.
Blaschko H. The natural history of amine oxidase. Rev Physiol Biochem Pharmacol. 1974; 70:83-148.
Knoll J. Memories of my 45 years in research. Pharmacol Toxicol. 1994; 75(2):65-72.
Knoll J. (-)Deprenyl (selegiline), a catecholaminergic activity enhancer (CAE) substance acting in the brain. Pharmacol Toxicol. 1998; 82(2):57-66.
Knoll J, Magyar K. Some puzzling pharmacological effects of monoamine oxidase inhibitors. Adv Biochem Psychopharmacol. 1972; 5:393-408.
López-Muñoz F, Alamo C. Monoaminergic neurotransmission. The history of the discovery of antidepressant from 1950s until today. Current Pharm. Des. 2009; 15(14):1563-86.
Sanacora G, Treccani G, Popoli M. Towards a glutamate hypothesis of depression: an emerging frontier of neuropsychopharmacology for mood disorders. Neuropharmacology. 2012; 62(1):63-77.
Schildraut JJ. The catecholamine hypothesis of affective disorders: a review of supporting evidence. Am J Psychiatry. 1965; 122(5):509-22.
February 27, 2020