Joseph Knoll: The Discovery of Enhancer Regulation in the Mammalian Brain

Joseph Knoll’s reply to Hector Warnes’ comment

Thank you Dr. Warnes for your thought-provoking comments.

Reply to “Innate versus acquired drives”

You ask me, how I separate drives from instincts. I never use the terms ‘instinct, instinctive’. Mammalian behavior is fully comprehensible via the careful analysis of the operation of inner drivesin the service of a limited number of goals of vital importance, indispensable for the survival of the individual and species (maintenance of homeostasis, fight and flight for survival, feeding, sexuality, progeny care, etc.), and the acquired drivesin service of an unlimited number of goals of not vital importance, dispensable for the survival of the individual and species.

An acquired drive always originates in one way or another from an innate drive, which relation later becomes unrecognizable, thus, nothing exists in the brain without a rational origin. With the elaboration of the “glass cylinder seeking drive” (see inhn.org, Definitions), we hit upon the right method to study in rats the process of fixing an acquired drive. In contrast to the rat, the mouse is unable to fix the glass cylinder seeking drive in the brain, which already suggests that the last step of crucial importance in the development of the mammalian brain was the appearance of the ability to fix acquired drives.

Vertebrates can be divided into three groups according to the mode of operation of their brain: (a) those which operate with innate drives only (the majority), (b) those with a limited ability to fix acquired drives (a minority); restricted manipulability of their behavior make them domesticable, and (c) the only one with unrestricted ability to fix acquired drives (Homo sapiens sapiens); thus, the manipulability of human behavior is infinite.

With the evolution of brains capable of acquiring drives, species appeared whose members could manipulate each other’s behavior and act together. This was the condition sine qua non for the evolution of social living, a form of life that enabled the social group to qualitatively surpass the performance of the individual. It goes without saying that the training of skills to act in concert radically improved the quality of life. With the development of the human brain, a functional network with over 100 billion interrelated nerve cells and 10¹¹ bit capacity arose. With this network, and with  the inexhaustible capacity of the human brain to acquire drives, from the operation of which conscious perception is inseparable, life on earth reached the most sophisticated form of appearance. Furthermore, human beings, primarily social creatures, are building blocks in the creation of a gigantic product: human society, which represents the highest form of life on earth.

Since the human brain is born with the ability to envision a non-existing world but hasn’t the foggiest idea how the world around him functions, creation of the still operating myths-directed human society could not be avoided. However, in order to survive, it was compelling to learn how the real world is functioning. To the end of the 18^th century, general knowledge progressed to a critical level. Since the age of enlightenment due to revolutionary changes in society (separation of Church and State), science and technology developed from strength to strength. Mankind strives after the final state: the rationally organized human society, grounded fully on scientific knowledge. Only a future global change in education, one based on the exact knowledge of the brain mechanisms responsible for the manipulation of human behavior, can finally lead to rationally directed society and terminate the still existing era where one hand destroys what the other hand has created.

Reply to “Deprenyl as an antidepressant, anti-Parkinson and anti-aging agent”

Reading your sober analysis regarding the therapeutic efficiency of a 10 mg daily dose of Selegiline/(-)-deprenyl (DEP) as an antidepressant and anti-Parkinson agent, interpretation is needed for why DEP, described in literature first in 1964, and now registered in more than 60 countries, marketed under more than 100 trade names, published in thousands of papers, still attracts attention. The recognition of the unique, complex pharmacological spectrum of this compound in three consecutive phases: the first in the 1960s, the second in the 1970s, and the third in the 1990s, each presenting a previously unknown and therapeutically useful effect, explains the peculiar development of the DEP-story.

DEP was synthetized in the early 1960s. The new compound first attracted attention as the unique MAO inhibitor, free of the cheese effect.

In the 1970s, DEP draw international attention as the first selective inhibitor of B-type MAO. The therapeutic daily dose of the drug is still 5-10 mg, the dose which blocks MAO-B in the brain.

In the 1990s, as summarized in my essay, the discovery of the catecholaminergic and serotoninergic enhancer regulation in the mammalian brain; the realization of β-phenylethylamine (PEA) and tryptamine as natural enhancer substances;  the identification of DEP as the first PEA-derived synthetic enhancer substance; and the development of (2R)-1-(1-benzofuran-2-yl)-N-propylpentane-2-amine (BPAP), a tryptamine-derived synthetic enhancer substance, opened a promising new  brain research domain.

A bi-modal, bell-shaped concentration effect curve is characteristic of the enhancer substances. As shown in Fig. 12, the optimum rat dose of DEP’s ‘specific’ enhancer effect is 0.001 mg/kg and 0.25 mg/kg is the peak dose of the ‘non-specific’ enhancer effect.  It deserves attention that the usually used 0.25 mg/kg DEP was selected to block completely MAO-B activity in the rat brain, and the therapeutic daily dose of DEP, 5-10 mg, was selected to block completely MAO-B in human brain. Thus, the human dose very likely has a second, overlooked effect: it exerts the non-specific enhancer effect of DEP. The share of the two simultaneously acting effects in the observed therapeutic benefits in humans treated daily with 5-10 mg DEP needs careful exploration. Fig. 24 shows that BPAP, the most potent synthetic enhancer substance, exerts the specific enhancer effect in a dose as low as 0.0001 mg/kg, and 0.05 mg/kg is the peak dose of the non-specific enhancer effect.

The realization that during the uphill period of life,from weaning until sexual maturity, enhancer regulation in the catecholaminergic and serotonergic neurons works on a higher activity level, sexual hormones terminate the hyperactive phase, and this change is the beginning of the downhill period of life, seems to me to throw light on the essence of brain aging (Tables 3-7).

Maintenance on a low dose of DEP slows the decay of the brain engine’s enhancer regulation. This safe preventive measure results in age-retarding, mental-energizing, performance-enhancing and longevity-promoting effects. Thus, it is not by chance that one finds on the internet a sea of enthusiastic reports on the benefits of taking daily 1 mg DEP as a prophylactic agent to slow brain aging. It is unfortunate that the implementation of a proper trial on healthy volunteers to measure exactly the anti-aging effect of DEP is still greatly needed.

The neurodegenerative diseases are incurable. We need to prevent or at least delay their manifestation. DEP is for sure primarily a catecholaminergic activity enhancer (CAE) substance. 1mg DEP daily slows the aging related decline of the catecholaminergic brain engine, thus improves the quality and prolongs the duration of life and may significantly delay the manifestation of neurodegenerative diseases.

Reply to “Theories that would be compatible with L’Deprenyl’s anti-aging effect”

I followed your analysis with keen interest and thank you for your reasonable proposals for future research. Let me briefly summarize in light of our findings our present knowledge regarding the basic mechanism of the enhancer effect.

We selected the optimum doses of BPAP for the longevity study in shuttle box experiments using laboratory rats. The essence of the in vivo analysis was the measurement of the acquisition of a two-way conditioned avoidance reflex (CAR) in the shuttle box, and the inhibition of rats’ learning ability with tetrabenazine-treatment (1 mg/kg sc.) which reversibly blocks the vesicular monoamine transporter 2 (VMAT2). Tetrabenazine depletes at least 90% of norepinephrine and dopamine from their stores in the nerve terminals within 1 hour. The lower the degree of saturation in the transmitter pools the lower is the excitability of the neuron. Due to the weak performance of the catecholaminergic brain engine, activation of cortical neurons remains in tetrabenazine-treated rats below the level required for acquisition of a CAR. However, addition of 0.0001 mg/kg BPAP to 1 mg/kg tetrabenazine fully restored the learning ability of the rats(see 1.9 in essay, demonstrating that BPAP restored full activity of the catecholaminergic neurons in the presence of tetrabenazine.

It is worth mentioning in this context that DEP’s protecting effect against a row of neurotoxic agents (6-OHDA, MPTP, DSP-4, AF64-A) is well known; and as shown in Fig. 12 DEP-treatment is also effective against tetrabenazine. Thus, the enhancer substances seem to transform the excitability of the enhancer sensitive neurons in a way that they are able to overpower various forms of neurotoxins.

It is common knowledge from electrophysiological studies with rodents and primates that the excitability and function of dopaminergic neurons are silent or spontaneously active. DEP or BPAP treatment keeps the catecholaminergic neurons on a higher activity level (Table 1-2 and Table 10-11). For example: 6.8 ± 0.18 nmol/g wet weight dopamine was released within 20 min from the substantia nigra isolated from saline treated rats and 14.8 ± 0.36 nmol/g wet weight dopamine was released within 20 min from the substantia nigra isolated from rats treated with a single dose of 0.0001 mg/kg BPAP. Similarly, a single dose treatment with 0.0005 mg/kg BPAP increased the release of norepinephrine from the isolated locus coeruleus within 20 min from 4.7 ± 0.10 (saline) to 15.4 ± 0.55 nmol/g wet weight; and a three-week treatment once daily with 0.0001 mg/kg BPAP acted similarly (the brain areas were isolated 24 hours after the last injection) (Table 10). These results furnish evidence that the treatment of rats with 0.0001 mg/kg BPAP transformed the silent catecholaminergic neurons into spontaneous firing entities.

Lifelong preventive medication obviously requires unique drug-safety. Due to their peculiar mechanism of action and safety margin, only the synthetic enhancer substances meet this requirement). BPAP exerts its specific enhancer effect in a subcutaneous dose as low as 0.0001 mg/kg, and 20 mg/kg, a 20-times higher dose is tolerated without any sign of toxic effect. This is truly an exceptional safety margin.

At present, DEP is the only synthetic enhancer drug in world-wide clinical use. In research and therapy, DEP celebrates a 50-year history. Very many patients are still treated permanently with the usual daily dose (10 mg) of DEP, as well as those who take 1 mg DEP daily to slow the aging-related decay of their catecholaminergic brain engine. They may slow, unaware, many unknown enhancer-sensitive mechanisms which pay a role in the improvement of the quality of life and longevity.

Joseph Knoll

July 14, 2016