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Tuesday, 20.03.2018

Joseph Knoll: Enhancer Sensitive Brain Regulations and Synthetic Enhancers (Selegiline, BPAP) Which Counteract the Regressive Effects of Brain Aging




          It is a horrifying fact that in Germany’s history millions of average normal people who had previously lived honest simple lives and had never belonged to extremist groups, dramatically changed within a few years after 1933. Imbued with Nazi ideology, they became unbelievably complicit in the murders of innocent civilians during World War II. This phenomenon has been documented from numerous perspectives in dozens of novels, films, and so forth.             However, an adequate elucidation of the brain mechanisms responsible for this dramatic and rapid behavioral change of millions has not yet been unearthed. It is worth considering that the manipulability of human behavior is obviously independent from the general cultural level of a society. For example, Germany produced numerous contributions to science and art and the average education level was well established already by World War I. Only one recruit out of 1,000 was illiterate in Germany, versus 330 in Italy, 220 in the Austrian-Hungarian Monarchy and 68 in France.

            As a survivor of Auschwitz and the Dachau death train, I directly experienced a few typical representatives of manipulated fanatics (Dunn 1998). I have had ample time and primary experience to reflect upon the essential changes in the physiological manipulability of the human brain. My life work was not a mere chance.

            When I started my behavioral studies in the early 1950s, I was planning to investigate how rats acquire an unnatural drive. I succeeded in developing a rat model to exactly study the nature of the brain changes in the course of the acquisition of an acquired drive from the start of training until its firm manifestation. I soon realized that this cortical mechanism explains the manipulability of more sophisticated mammalian organisms. Two enthusiastic students, Károly Kelemen and Berta Knoll, now distinguished scientists, joined me in this work. Since I began my own laboratory many decades ago, I never left it for longer than a month and worked with my best co-workers for decades.

            In 1945, I matriculated at the Pázmány Péter University, Faculty of Medicine, Budapest (from 1951 University of Medicine, Budapest; from 1969 Semmelweis University of Medicine; and from 1999 Semmelweis University). In 1949 I was invited by Professor Bela Issekutz (1886-1979), Head of the Department of Pharmacology, to join his research staff.
I began working there as a student in February 1949. After Professor Bela Issekutz retired, I was the Head of the Department from 1962 until 1992. I began working in 1949 in the original building of the Department of Pharmacology and we moved into a new building in 1978, where I am still working, now as Emeritus Professor of Pharmacology. The Department changed its name to the Department of Pharmacology and Pharmacotherapy in 1999.

            Until the end of the 1960s, the role of acquired drives in the mammalian brain was in the center of my interest. I summarized the results after a 16-year research period in my first monograph (Knoll 1969).

            In the 1970s, a new period of my research began with the discovery of the enhancer-sensitive regulations in the mammalian brain. I selected the catecholaminergic and serotonergic neurons as enhancer-sensitive models for detailed analysis. Two synthetic enhancers, specified to the selected models: (R)-N-methyl-N-(1-phenylpropan-2-yl)prop-2-yn-1-amine (Selegiline/(-)-deprenyl) (DEP), the β-phenylethylamine (PEA)-derived synthetic enhancer substance and (2R)-1-(1-benzofuran-2-yl)-N-propylpentane-2-amine (BPAP), the tryptamine-derived much more potent synthetic enhancer substance than DEP, were developed. We can define the enhancer-sensitive brain regulations as: the existence of neurons capable of changing their excitability in milliseconds and working on a higher activity level, due to natural or synthetic enhancer substances. After 36 years of research, I summarized the results of this new line of research in a second monograph (Knoll 2005).

            We seek now to ascertain the full complexity of the enhancer-sensitive brain regulations, identify hitherto unknown regulations and further analyze how the synthetic enhancers counteract brain aging with the aid of synthetic enhancers. We demonstrated that during the developmental/young phase of life, from weaning until sexual maturity, the enhancer-sensitive neurons work on a significantly higher activity level and sexual hormones terminate the developmental phase and restore the enhancer regulations to the low, pre-weaning activity level. This is the beginning of the post-developmental/aging phase characterized by a slow, irresistible decline of the enhancer-sensitive brain regulations which continues until death. It is extremely important that the regressive effects of brain aging in mammals are primarily due to the age-related decline of the natural enhancer regulations.

            The unique pharmacological spectrum of DEP allowed me to discover in the mid-1990s the enhancer regulation in the mammalian brain. The realization of the catecholaminergic and serotonergic neurons’ enhancer-sensitivity and their selection as models to study the characteristics of the enhancer-sensitive brain regulations, brought to light unknown mechanisms of brain-aging in mammals during the post-developmental phase of their life.

            Finally, the development of synthetic enhancers rendered the countering of brain-aging possible, which has always been the main practical aim of my research.

            To demonstrate our recent success, I refer to our first experimental confirmation in a longevity study that life-long maintenance of rats from sexual maturity on a low dose of BPAP (0.0001 mg/kg), the selective, highly potent synthetic enhancer fully prevented aging of the dopaminergic neurons. The study proved that the slowly progressing, aging-related loss of the natural enhancers was responsible for the regressive effects of brain-aging. In dopaminergic neurons, the aging-related loss of PEA, the natural enhancer of the catecholaminergic neurons, leads to the aging-related loss of dopamine. We know, for example, that in the healthy human population, the calculated loss of striatal dopamine (DA) is about 40% at the age of 75. Essentially, the same percentages apply to rats (Knoll 2005).

            However, the enhancer-sensitive neurons do not age. This means that to prevent the aging of the dopaminergic neurons via substituting the lost natural enhancer with a synthetic enhancer substance after sexual maturity until death is a feasible possibility. We demonstrated this possibility in a longevity study with our new approach to fight brain aging.

            As published in 2016, we treated a group of rats from sexual maturity until death, three times a week, subcutaneously, with 0.0001 mg/kg BPAP, the peak dose which exerts the specific enhancer effect in rats. After an 18-month treatment, we measured the learning ability of the rats in the shuttle box. In perfect agreement with our preliminary findings, the longevity study presented evidence that BPAP-treatment completely prevented aging of the dopaminergic neurons. The learning ability of the aged rats was equal with the performance of the young, 3-month old saline treated rats, which are peaking in their learning ability. Since due to aging, the catecholaminergic neurons lost already a lot of their natural enhancers, aged, 18-month-old saline-treated rats retain only 30% of their learning ability compared to their 3-month-old peers (Knoll and Miklya 2016).

            This book is primarily devoted to analyze the pharmacological profile of the two presently available, safe synthetic enhancers: DEP and BPAP. Prior to the discovery of the enhancer-sensitive brain regulations and the development of the synthetic enhancer substances, it was entirely unimaginable to safely counteract the regressive effects of brain aging. As it will be shown in detail in this monograph, the enhancer-sensitive catecholaminergic and serotonergic neurons work in human and animal models similarly, and regarding the mechanism of the enhancer effect, we could not detect any qualitative difference between DEP and BPAP.

The primary aim of my book is to motivate clinicians to test whether synthetic enhancers can counteract brain aging in healthy humans similarly as shown in our recent paper in aged rats (Knoll and Miklya 2016).



Dunn S, editor. Dachau 29 April 1945, The Rainbow Liberation Memories. Lubbock: Texas Tech University Press; 1998.

Knoll J. The theory of active reflexes. An analysis of some fundamental mechanisms of higher nervous activity. Budapest: Publishing House of the Hungarian Academy of Sciences, New-York: Hafner Publishing Company; 1969.

Knoll J. The brain and its self. A neurochemical concept of the innate and acquired drives, Berlin, Heidelberg, New-York: Springer; 2005.

Knoll J, Miklya I. Longevity study with low doses of selegiline/(-)-deprenyl and (2R)-1-(1-benzofuran-2-yl)-N-propylpentane-2-amine (BPAP). Life Sci 2016; 167: 32-8.


February 22, 2018