Tuesday, 21.11.2017

Joseph Knoll: The Discovery of the Enhancer Regulation in the Mammalian Brain and the Development of the Synthetic Enhancer Substances 

Hector Warnes’ comment

 

            I don’t really feel qualified to dissect Professor Knoll’s great contribution.  He is a basic scientist with findings in animal and human research which support his views. I am a clinician with interest in this particular area of research.

 

I am glad that Professor Knoll has addressed three important issues in his “history of enhancer regulation”:

1.       Innate versus acquired drives.

2.       L-Deprenyl as an antidepressant, anti-Parkinson and anti-aging agent.

3.       Theories that would be compatible with the anti-aging effect of L-Deprenyl.

 

1. Innate versus acquired drives

I would like to start my comments by citing Konrad Lorenz: “Instinctively innate and individually-acquired links often succeed each other directly in the functionally uniform action chains of higher animals. I have termed this phenomenon ‘instinct training interlocking’ and emphasized that similar interlocking also occur between instinctive and insightful behavior” (Lorenz 1957, p. 137). Further, Lorenz asserts that complex behavior patterns in higher animals and men, which are built on an instinctive basis but are imbued with learned or acquired components, would be considered an example of interlocking. Professor Knoll suggests that innate drives are released by the mesencephalic- and acquired drives by the telencephalic- brain.  I would be interested to know how he separates drives from instincts?

            Professor Knoll has experienced in his own flesh and mind the atrocities committed by the Nazis.  Like any totalitarian regime, the Nazis shared a high degree of fanaticism which they displayed with a vengeance and readiness to respond to specific stimuli by invoking a combination of numerous interlocking functions (innate releasing mechanism). Freud (1921) thought that the group mind often obliterates an individual’s acquired values.   Once the individual is united with the group, it unleashes in him a frenzy of enthusiasm and his most blunt and primitive side. In that collective mentality, one may acquire a feeling of invincible power while caught in the discourse with the leader in a unique altered state of consciousness. The action of the masses transforms and drives (contagion) and under this action one becomes pray of great suggestibility. The mutual tie between members of a group is in the nature of identification with the leader.

Professor Knoll, himself a survivor of the Holocaust, rose to greatness as a scientist in spite of the severe traumas which he endured, including persecution, torture, hunger and loss of most of his family in concentration camps (Lager). He is living example of resilience and innate capacity to overcome (überwinden) the most traumatic experiences that a man can endure (Knoll 2005).

 

2. L-Deprenyl as an antidepressant, anti-Parkinson and anti-aging agent           

On March 13, 2014 Miklya Ildiko (2014) wrote an outstanding review on Selegiline that was posted on the INHN website. ‘Deprenyl or selegiline was developed by Professor Knoll and his team at Semmelweis University in Budapest, Hungary. It was patented in 1962 and its levo-rotatory enantiomer compound was discovered in 1967.  

L-Deprenyl is an irreversible inhibitor of MAO-B. It has dopaminergic and catecholaminergic effects and unlike the MAO-A inhibitors it does not produce the ‘cheese effect’ (tyramine). However, in doses over 20 mg l-Deprenyl loses its selectivity and inhibits both the MAO-A and MAO-B enzymes. In a dosage of 5mg l-Deprenyl inhibits the MAO-B enzyme by 90%. 

 It was shown that l-Deprenyl was useful in in the treatment of Parkinson’s disease. In one study, by its dopaminergic effect it delayed the need to introduce L-Dopa treatment by 13 months. The adverse side effects of Selegiline in low doses are nausea and insomnia. 

There has been an underutilization of L-deprenyl by clinicians perhaps for fear of side effects and length of ‘wash out’ time needed in case of emergency procedures. Until the early years of the 21st century, Selegiline in the doses from 5mg to 10mg per day orally was not found particularly effective in the treatment of major depressive disorders but useful in some cases of atypical depression and dysthymic disorders.  

 

 There was an early optimism followed by disappointment about its use as an antidepressant about 15 years ago. J. Alexander Bodkin at the McLean Hospital used Selegine as a transdermal patch that was approved by the US Food and Drug Administration for the treatment of depression, in 2006. Bodkin treated 177 depressed patients with the transdermal patch; 89 wore patches with the active compound and 87 wore patches with no drugs.  After 6 weeks, those patients who wore patches with the active compound had a remission rate of 42 % (37 patients). However, this significant results were not replicated in other clinical research (Cromie. 2002). In so far as I am aware, there was no comparative study of l-Deprenyl’s efficacy in the treatment of depressive disorders with established antidepressant compounds, such as desvenlafaxine, mirtazapine, duloxetine, fluoxetine, agomelatin, bupropion and so on.  Bupropion has a metabolite closely related to phenethylamine, an endogenous amphetamine. 

The transdermal preparation acts almost exclusively in the brain. By passing hepatic metabolism and the elimination of the drug via the gut, it offers advantages in the treatment of some depressive disorders (Stahl 2011).

The original research of Professor Knoll on aging with l-Deprenyl showed a doubling of life-span in Wister-Logan rats.  When other investigators tried to replicate the study they did not obtain the same results when using different strains of rats. This difference indicates that in longevity, genetic mechanisms are involved.  

It is reasonable to assume that in the future it will become possible to determine by positron emission tomography (PET) the functional lesion in the nigrostriatal catecholaminergic neurons, the subclinical onset of Parkinson’s disease and to delay the appearance of its clinical manifestations by the administration of l-Deprenyl.  Perhaps the same will be the case for Alzheimer’s disease when biological markers (amyloid plaques, apolipoproteins and protein Tau plus imaging) will become available for detecting high risk asymptomatic patients.

Peter Franz Riederer and his team in Vienna were one of the first researchers in 1975 who tried to replicate Professor Knoll’s findings (Gerlach,Youdim, Riederer 1996).  Professor. Riederer’s findings were supportive of Professor Knoll’s view that selegiline has neuroprotective activity.

 

3. Theories that would be compatible with the antiaging effect of L-Deprenyl

The first longevity study of Professor Knoll with l-Deprenyl, was published in 1988. Knoll considers phenylethylamine and tryptamine “natural enhancers” which delay theonset of brain decline. Several decades after the discovery of l-deprenyl, Knoll discovered another enhancer substance, R-1-benzofuran-2-yl-2-propylaminopentane (-)-or BPAP.

With aging, there are signs of entropy which lead to irreversible changes and eventually to death. Biological organisms show spontaneous fluctuations and by losing homeostasis become highly unstable dynamical systems.  The changes which are taking place from conception to death include mutations of mitochondrial DNA with gradual accumulation of cells which are bio-energetically deficient. Mitochondrial dysfunction with the over-production of free radicals are paramount in the aging process. Our natural genetically determined life span might be altered also by epigenetic factors including the accumulation of molecular damage caused by the production of metabolically and environmental triggered free radicals, chromosomal mutations and nutritional factors. Obviously the wear and tear of life itself plays a very important role in aging.

It would be interesting to test the ‘enhancer’ effect of l-Deprenylon the length of the telomeres (TTAGG hexanucleotides). The function of the telomeres is the protection of chromosomal deoxyribonucleic acid (DNA) from alterations. The length of telomeres is associated with the biological clock. We lose about 41 pairs per year. (Those Down’s syndrome patients lose 133 pairs per year). Telomerase protects the chromosomal length by nurturing it with nucleotides. It is possible to determine whether one has a gradual decline of telomerase or a speedy decline.  In case of “speedy decline”, ‘enhancer treatment’ (that increases neurotransmitter activity) might reverse the process.  

It was shown that  l-Deprenyl like other antidepressants increase the Brain Derived Neurotrophic Factor and or the Nerve Growth Factor  which act by their effect on neural plasticity-neurogenesis (like other antidepressants and  anti-oxidants) hindering apoptosis and cellular  death.

There is plenty of evidence that Delta sleep decreases gradually with age accompanying a decrease of growth hormone production and immunity. With immuno-incompetence there is an increase of infections, auto-immune disorders and cancer. During Delta sleep the brain uses less energy and restores its supply of adenosine triphosphate (ATP) (Besedowsky, Lange, Born 2012).   

I must congratulate Prof. Knoll for his life work that has provided a new path to slow aging to the inevitable end.

 

References

Besedowsky L. Lange T, Born J. Sleep and immune function. Pflugers Arch 2012; 463   (1): 121-7.  

Cromie WJ. Bodkin is patching up depression. Harvard University Gazette, November 7, 2002.

Freud S. Group psychology and analysis of the ego The Standard Edition vol. XVIII, London: Hogarth Press; 1921.

Gerlach M. Youdim MBH, Riederer P.  Pharmacology of selegiline. Neurology 1996; 47 (suppl.3). 2137-45.

Knoll J. The Brain and Its Self: a Neurochemical Concept of Innate and Acquired Drives. Heidelberg: Springer; 2005..

Lorenz K. Studies in animal and human behavior. In: Schiller F, editor. Instinctive Behavior. New York: International University Press; 1957.

Miklya I. The history of Selegiline. The first MAO-B inhibirtor and the first synthetic enhancer regulator substance. International Network for the History of Neuropsychopharmacology, Archives. March 13, 2014

Stahl SM. Essential Psychopharmacology. Fourth edition. Cambridge: Cambridge University Press; 2011.

 

Hector Warnes

May 19, 2016