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


Chapter 11



     Personal endeavors motivated me to plan rat and mouse experiments in order to investigate the mechanism responsible for the manipulability of mammalian behavior. The realization in the 1950s that the inborn ability of rats’ cortex to fix acquired drives is responsible for the manipulability of their behavior was the first significant discovery in my research.

     In contrast to innate drives with a limited number of indispensable (life important) goals, acquired drives are responsible for an unlimited number of dispensable goals. The capability to acquire an insuppressible urge for a goal which is not necessary for survival of the individual or species represents the most sophisticated function of the telencephalon.

     Vertebrates can be divided into three groups according to their brains’ mode of operation: (a) those that operate with only innate drives (the majority); (b) those with an ability to acquire drives (a minority); and (c) the “group of one” that operates almost exclusively with acquired drives (Homo sapiens). The mouse, a rodent closely related to the rat, trained under the same experimental conditions as the rat, was unable to acquire the glass-cylinder-seeking drive, demonstrating that the development of mammals with a brain capable to fix acquired drives possess a qualitatively higher developed brain than the mammals devoid of this ability.

     The development of an acquired drive always originates in one way or another in an innate drive proving that nothing exists in the human brain without a rational origin

     With the evolution of brains capable of acquiring drives, species appeared whose members could manipulate each other’s behavior and act in concert. This was the condition sine qua non for the evolution of social living, a form of life that enabled species to surpass qualitatively the performance of any given individual. Unquestionably, members in the skills needed to act in concert with each other improved the quality of life. The evolution of mammalian brains with the ability to acquire drives made the appearance of life on earth so immensely variable (Knoll 1969).

     The discovery of the enhancer-sensitive brain regulations; the selection of the catecholaminergic and serotonergic neurons to analyze their characteristics; the identification of β-phenylethylamine (PEA) for the catecholaminergic neurons and tryptamine for the serotonergic neurons as natural enhancers; and the development of selegiline/(-)-deprenyl (DEP), the PEA-derived synthetic catecholaminergic activity enhancer (CAE) substance and (2R)-1-(1-benzofuran-2-yl)-N-propylpentane-2-amine (BPAP) the tryptamine-derived synthetic enhancer substance, catalyzed the discovery of the unique ability of the synthetic enhancers to prevent brain-aging.

     The average human lifetime is rapidly lengthening and is already around 90 years in developed countries. It is imperative to counteract the regressive effects of brain aging which embitter the life of the aged. To reach this aim, it was an important discovery to realize, on the one hand, that the fading stimulation of the natural enhancers plays the key role in brain aging, and on the other hand, that the enhancer-sensitive neurons do not age. Due to permanently intensified enhancer-sensitive brain regulations, young mammals are vigorously mobile during the developmental period of life from weaning until sexual maturity. Sexual hormones immediately restore the pre-weaning low level of the enhancer-sensitive brain regulations and thus put the post-developmental (aging) phase in motion. Due to slow, unbroken loss of the natural enhancers over time, brain functions are subject to an aging-related continuous decline and the regressive effects of brain-aging grow until death. Since we clarified that the aging-related loss of natural enhancers are responsible for brain-aging, but the enhancer-sensitive neurons do not age, DEP and BPAP, the already developed synthetic enhancer substances prevent the regressive effects of brain aging.

     DEP was described first as the selective inhibitor of MAO-B. It has been known since 1988 that mammals treated with 0.25 mg/kg DEP, which blocks MAO-B activity in the brain, live significantly longer than their saline treated peers. The first longevity study performed with low doses of DEP and BPAP, demonstrating that the enhancer effect is responsible for life extension was published in 2016 [4]. We presented experimental evidence that the enhancer-sensitive catecholaminergic neurons in rats treated from sexual maturity until death with 0.0001 mg/kg BPAP kept their unchanged learning ability.

     We treated rats daily with saline versus 0.0001 mg/kg BPAP and measured in the shuttle box their ability to fix a conditioned avoidance reflex (CAR). Due to aging of the catecholaminergic (primarily dopaminergic) neurons, the rat’s learning ability is subject to age-related decline. We found in this study that the young, 3-month-old group of saline-treated rats worked with full capacity in the shuttle box and built on the fifth day of training an average nearly 90% of the possible 100% of CARs. Due to aging 18-month-old saline-treated rats reached on the fifth day of training an average only less than 30% of the possible 100% of CAR.

     However, BPAP-treatment counteracted the aging-related decline in learning ability. The group of 18-month-old rats treated from sexual maturity with 0.0001 mg/kg BPAP produced on the fifth day of training an average of more than 90% of the possible 100% of CARs. This is an unprecedented novelty, unquestionably an unparalleled drug effect, proving that the synthetic enhancer substituted the lost natural enhancer, and thus fully prevented the aging-related learning deficit.

     BPAP, the selective and most potent synthetic enhancer, is preferentially used as a specific marker to detect hitherto unknown enhancer-sensitive brain regulations. A longevity study performed with low doses of DEP and BPAP detected the operation of an enhancer-sensitive tumor-manifestation-suppressing (TMS) regulation in the rat brain. This was the first discovery of a previously unknown enhancer-sensitive brain regulation (Knoll 1993).

     Lifelong preventive medication obviously requires unique drug-safeness. Due to their peculiar mechanism of action and safety margin, only the synthetic enhancer substances adhere to this requirement. BPAP exerts in rats its specific enhancer effect in a subcutaneous dose as low as 0.0001 mg/kg, and 20 mg/kg; a 20.000 times higher dose is tolerated without any sign of toxic effect. This is truly an exceptional safety margin and calls for a reasonable trial to test in humans whether synthetic enhancers can counteract brain aging in healthy humans as shown in our recent paper on rats (Knoll and Miklya 2016).


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

Knoll J. The pharmacological basis of the beneficial effect of (-)deprenyl (selegiline) in Parkinson's and Alzheimer's diseases, J. Neural Transm. 1993;Suppl 40:69-91.

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;167:32-38.


June 6, 2019