(adapted from Mavericks of Medicine, Smart Publications)
Joseph Knoll, M.D., a Hungarian neurochemist and pharmacologist probably best known for developing the drug deprenyl (Selegiline), the first selective monoamine oxidase-B (MAO-B) inhibitor, has researched its properties for more than half a century.
Dr. Knoll’s recently published book, The Brain and Its Self: A Neurochemical Concept of Innate and Acquired Drives (Springer, 2005), summarizes his life’s research and his fascinating speculations about the relationship between brain activity and culture. Dr. Knoll describes how his experience as a Nazi concentration camp survivor helped inspire and motivate much of his scientific research. Although his parents were sent to the gas chamber when he was a teenager, Dr. Knoll survived because he spoke fluent German and was chosen to serve as the personal servant to the Chief of the SS guards. In 1945, after the war, Dr. Knoll returned to his native city of Budapest. He earned his M.D. from the University of Budapest in 1951, and later became a professor and the head of the Department of Pharmacology at the Semmelweiss University of Medicine in Budapest.
In the early 1950s, Dr. Knoll helped to pioneer research into the physiological basis of innate and acquired drives in animals. Trying to make sense of his experience in the Nazi concentration camp, Dr. Knoll became interested in how animals acquire new drives. The research that resulted from Dr. Knoll’s interest in this subject centered around studying the brain changes in rats that had been trained to have an acquired drive for an unnatural object—a glass cylinder. This acquired drive—which urged the animals to search for, and jump to, the rim of a thirty centimeter-high glass-cylinder, and then crawl inside—would often override the animals’ instinctive drives for food and sex.
Deprenyl Protects Cognitive Function via Several Distinct Mechanisms
First synthesized by Dr. Knoll in his Budapest laboratory in 1961, deprenyl induces irreversible inhibition of MAO-B, thus increasing the availability of dopamine, particularly in the substantia nigra, in which dopamine-producing neurons degenerate in Parkinson’s disease.1 Increased MAO-B activity also plays a role in the age-related loss of cognitive function. Neuron loss in the aging brain is accompanied by a proliferation of glial cells, in which MAO-B activity is increased, promoting the decline in dopaminergic modulation seen in senescence.2
In addition to its action as a selective MAO-B inhibitor, deprenyl enhances catecholaminergic activity by stimulating the coupling of action potential to transmitter release in catecholaminergic neurons, while also selectively enhancing superoxide dismutase (SOD) and catalase activity in the striatum, thus protecting dopaminergic neurons against oxidative stress and neurotoxins.3 4
The combined effect of these protective actions is significant support for the maintenance of neurological function, and deprenyl has demonstrated efficacy in the treatment not only of Parkinson’s disease, but Alzheimer’s disease, other dementias and depressive disorders.5 6 7 8 9 10
Improvements in Cognitive Performance
Although primarily prescribed to help people with Parkinson’s disease, memory disorder problems, and depression, deprenyl has also been shown to boost mental performance. In animal studies, deprenyl has improved cognitive performance in middle-aged rats and reversed cognitive impairments in aged rats.11 12 When given to young animals, chronic administration of deprenyl enhances neuroplasticity and improves learning behavior as effectively as rearing in an enriched environment.13 Deprenyl has also been shown to promote cognitive recovery after brain injury, facilitating noradrenergic fiber integrity and enhancing synaptic plasticity in the hippocampus.14 Combined with other cognitive enhancers, such as hydergine and piracetam deprenyl has significant potential for enhancing memory, intelligence, and concentration. (For an excellent summary of current research in this area, see Morgenthaler J, Dean W, Smart Drugs and Nutrients II.).
Enhancement of Sexual Function
Deprenyl has also been shown to enhance sexual function, a not unexpected side effect since brain dopaminergic mechanisms are involved in the regulation of sexual behavior. Activation of dopamine receptor sites, with resultant release of oxytocin from the paraventricular nucleus of the hypothalamus, induces sexual arousal and erectile responses in both experimental animals and humans.15 Dr. Knoll and colleagues first reported indications for deprenyl’s potential as a sexuality enhancer in 1983, with reports that old male rats dramatically increased their “mounting frequency” and “intromission” when treated with deprenyl in comparison to untreated animals. In humans, deprenyl’s beneficial effects on sexuality have been reported in patients with major depressive disorder; treatment with deprenyl produces significant improvement in sexual interest, arousal, and satisfaction.16
Extension of Maximum Life Span
Deprenyl has also been shown to increase the maximum lifespan of laboratory animals by close to 40%. Giving deprenyl to animals is the only experimental treatment—besides caloric restriction—that has been shown to increase maximum life span.17 18 19 20
To fully appreciate how significant deprenyl’s life extension potential is, one has to understand the difference between maximum life span and average life span. Many factors can affect an animal’s average lifespan (i.e., normal life expectancy) including genetics, diet, exercise, nutritional supplements, and mental attitude. However, even under the very best of conditions, there is an upper limit to which the longest-lived animals of a particular species can survive, and this is the animal’s maximum life span.
The average life span of a human being is approximately 70 to 80 years. However, the maximum life span of a human being is around 120 years. The laboratory animals in the deprenyl studies showed a 40% increase in maximum life span, the human equivalent of living 150 years. Since deprenyl’s mechanisms of action are the same in all mammalian brains, its life extension effects have a high likelihood of affecting humans, just as its mental benefits do.
Deprenyl is extremely safe, resulting in fewer side effects than placebo in numerous studies. Unlike other MAOIs, dietary restrictions are typically unnecessary for deprenyl. When taken at moderate levels (under 10 mg/day), deprenyl selectively inhibits MAO-B, and therefore does not interfere with the body’s ability to metabolize tyramine, as do non-selective MAOIs, such as phenelzine (Nardil). For this reason, deprenyl does not have the potential side effect of triggering a hypertensive reaction if tyramine-rich foods, such as cheese or wine, are consumed.21 22 23
An Interview with Dr. Knoll
Following are some excerpts from an interview conducted with Dr. Knoll, who, born in 1925, was 80 at the time. Dr. Knoll spoke about how his experience with the holocaust influenced his decision to become a research scientist, how people can utilize deprenyl for its cognitive enhancing and anti-aging benefits, and what type of anti-aging treatments might be available in the future.
Q: How did your experience with the holocaust when you were young influence your decision to become a research scientist, and what inspired your interest in neurochemistry?
Dr. Knoll: It is a horrifying fact that in Germany millions of single-minded little-men, who had previously lived an honest, simple life and never belonged to extremist groups, dramatically changed within a few years after 1933, and, imbued with the Nazi ideology, became unbelievably cool-headed murders of innocent civilians during the Second World War. This phenomenon has been documented from many angles in dozens of novels, films, and so on. However, we are still waiting for an adequate elucidation of the brain mechanism responsible for this dramatic and rapid change in the behavior of millions.
As a survivor of Auschwitz, and one of the 1,300 survivors of the “Dachau Death Train,” I had the opportunity to directly experience a few typical representatives of this type of manipulated human beings, and had more than enough time and direct experience to reflect upon the essential changes in the physiological manipulability of the human brain. It was therefore not just by mere chance that, when in the early 1950s I finally had the opportunity to approach this problem experimentally, I decided to develop a rat model to follow the changes in the brain in the course of the acquisition of a drive from the start of training until its manifestation.
Q: What are some of the disorders for which deprenyl has proven itself to be an effective treatment?
Dr. Knoll: Successful clinical studies with deprenyl were executed in depression and in the two age-related neurodegenerative diseases: Parkinson’s disease and Alzheimer’s disease. The first clinical study performed in depressed patients by Dr. Varga with deprenyl was published in 1965. The clinical use of deprenyl in Parkinson’s disease started in 1977. The first two papers demonstrating the effectiveness of deprenyl in Alzheimer’s Disease appeared in 1987. Deprenyl was originally developed with the intention to be used as a new spectrum antidepressant. Its effectiveness was first demonstrated with the racemic form of the compound by Dr. Varga and his coworkers in 1965 and 1967, and with the enantiomer in 1971. The first study that corroborated the antidepressant effect of deprenyl was published by Dr. Mann and Dr. Gershon in 1980.
The realization of the peculiar effect of deprenyl—first in Parkinson’s disease and later in Alzheimer’s disease—distracted attention from its antidepressant property which remains unutilized. Even an especially interesting aspect of this problem fell into oblivion. In a depression study performed by Dr. Birkmayer and his coworkers in 1984 on 102 outpatients and 53 inpatients, deprenyl was given together with phenylalanine. The latter is the precursor of phenylethylamine (PEA) that, in contrast to PEA, crosses the blood-brain barrier and, as it is metabolized in the brain, increases the concentration of this natural enhancer substance. Nearly 70% of the patients achieved full remission from depression. The outstanding clinical efficiency was equaled only with that of electroconvulsive treatment, but without the latter’s side effect of memory-loss.
Q: How might healthy people utilize deprenyl for its cognitive enhancing and antiaging benefits?
Dr. Knoll: They should take one milligram of deprenyl daily from sexual maturity until death.
Q: Some studies have shown that deprenyl can significantly increase the maximum life span of laboratory animals, yet some of the longevity researchers that I’ve spoken with told me that these findings have been difficult to replicate. Why do you think this is, and what are your thoughts about this?
Dr. Knoll: Our finding that deprenyl prolongs life was corroborated in mice, in rats, in hamsters, and in dogs. Nevertheless, variation in the extent of the prolongation of life between the longevity studies performed in different laboratories was unusually high. The reason for this variation is now clear. A bell-shaped concentration effect curve is characteristic to the enhancer effect of the synthetic mesencephalic enhancer substances. Thus, there is an optimal dose for the enhancer effect.
Concerning the optimal dose of deprenyl there are, not only species, but also strain differences. On the other hand, even the effect of an optimal dose depends on the selected experimental conditions. We worked, for example, with the long-lived, robust, Wistar-Logan strain, which seldom grows tumors. The age of rats at the start of treatment was two years in our first study and roughly eight months in our second study.
In both studies a substantial number of rats treated with deprenyl lived longer than the estimated technical life span of three and a half years.
Dr. Milgram and colleagues were the first who repeated our survival study with deprenyl. They clearly intended to hold tightly to the parameters we used in our first study, and started experiments with two year old rats and treated them with 0.25 milligrams per kilogram of deprenyl. They changed, however, an important parameter. They worked with the short-lived Fischer 344 strain of rats, thus, they started treatment too late and found only a 16% marginally significant prolongation of life span. Nevertheless, they found a convincingly significant increase in the longer survival.
Dr. Kitani and colleagues, who conducted the second control survival study with deprenyl, also used Fischer 344 rats. They obviously considered that these rats are shorter living than the Wistar-Logan rats, and they started to work with one and a half year old rats. This was an advantageous change in the experimental conditions and found a satisfyingly significant, 34% prolongation of the average life span.
However, in the hope to increase the effectiveness of their treatment, they doubled the dose of deprenyl. Although a higher dose is usually more effective than a lower one, the doubling of the dose was, in this special case, an unfavorable change. We know now that 0.01 milligrams per kilogram of deprenyl is sufficient to exert an enhancer effect. Thus the 0.5 milligrams per kilogram dose was obviously enormously high, and this explains why Kitani and colleagues found no sign of the significant extension in the longest survival which appeared in our studies and in the Milgram et al. study.
All in all, in future longevity studies with a synthetic mesencephalic enhancer substance, it is reasonable to treat the animals with a dose that in preliminary studies proved to exert a peak effect in enhancing the release of catecholamines and serotonin in the brain stem.
Q: What do you think are the primary causes of aging in general?
Dr. Knoll: Various species live together on earth in a harmonious proportion. This is obviously carefully regulated. One of the seemingly principal regulatory mechanisms that produces equilibrium among living organisms is brain aging. It ultimately leads to the elimination of those individuals who have already fulfilled their duty in nurturing the new generation.
Accordingly, the period from weaning until sexual maturity is reached is the most delightful phase of life, the glorious uphill journey. The individual progressively takes possession, on a mature level, of all abilities crucial for survival and maintenance of the species. It learns to avoid dangerous situations, masters the techniques to obtain its food, develops procreative powers for sexual reproduction and copulates.
This is, at the same time, the climax of developmental longevity. The fully sexually mature individual fulfills its duty. Thus, to maintain the precisely balanced out natural equilibrium among living organisms, the biologically “useless” individual has to be eliminated. According to the inborn program, the post-developmental stage of life (aging) begins. The essence of this stage is progressive decay of the efficiency of the catecholaminergic system during the post-developmental life span until at some point, in an emergency situation, the integration of the parts in a highly sophisticated entity can no longer be maintained and “natural death,” signaled by the disappearance of the EEG signal, sets in.
Q: What do you think are currently the best ways to slow down, or reverse, the aging process and extend the human life span?
Dr. Knoll: Regarding the quality and duration of life, the most important aging process is the continuous, slow, age-related decline of the mesencephalic enhancer regulation during the post-development phase of life. This can not be reversed, but its progress can be slowed by the prophylactic administration of a synthetic mesencephalic enhancer substance (for the time being, with the daily administration of one milligram of deprenyl). The earlier this protective treatment starts, the better are the prospects to improve the quality of life in the latter decades, which necessarily goes together with an extension of life span.
Q: How long do you think it’s possible for the human life span to be extended?
Dr. Knoll: The average life span in the most developed countries has already exceeded the eighty year level. This change has come about due to the prevention of premature deaths owing to the development of hygiene, immunology, and chemotherapy. The human technical life span (TLSh), close to one hundred twenty years, has remained, however, unchanged.
In my view, to extend the human life span beyond the TLSh needs the elaboration of an ultimate technique for the prophylactic, daily small-dose administration of a safe synthetic mesencephalic enhancer substance from sexual maturity until death. The attainable upper limit in the extension of the TLSh is obviously unpredictable at present.
Nevertheless, if brain research could, at some time in the future, achieve just a doubling of the TLSh, this will mean for humans the most significant accomplishment that science has ever achieved, since nothing can be more important for the individual than the quality and duration of his/her life.
Q: What are some of the new anti-aging treatments that you foresee coming along in the near future?
Dr. Knoll: In the developed countries, the proportion of the aged is high, and the estimated number of individuals over sixty-five will increase to 1.1 billion by 2050. Accordingly, the demand on anti-aging therapy is rapidly increasing. This trend explains the already high-sounding proposals for anti-aging treatments.
My view is that since the brain alone ensures that the mammalian organism works as a purposeful, motivated, goal-directed entity, the age-related changes in the central nervous system are of particular importance. And since the enhancer-sensitive neurons in the brain stem work as the engine of the brain, the slow, continuous, post-developmental functional decline of the mesencephalic enhancer regulation is of primary importance in the maintenance of the well-balanced equilibrium among living organisms, because it helps to eliminate the individuals who already fulfilled their duty in nurturing the new generation.
For the time being, the prestigious task—the maintenance of the mesencephalic enhancer regulation during the post-developmental phase of life on the enhanced level characteristic of developmental longevity—cannot be fully accomplished. However, it is already feasible to modestly slow the age-related decay of the catecholaminergic and trace-aminergic tone in the brain via the prophylactic administration of one milligram of deprenyl daily.
The development of BPAP—a synthetic mesencephalic enhancer substance that is at least a hundred times more potent than deprenyl—is by itself a hint that our present knowledge about the mesencephalic enhancer regulation is in a very early stage. The high potency of BPAP indicates already that much more potent natural enhancer substances than PEA and tryptamine might exist. Better understanding of mesencephalic enhancer regulation promises to develop more efficient techniques in the future to slow brain aging and prolong human life beyond the TLSh. According to my judgment, this is the only physiologically well-founded, feasible, anti-aging therapy that I foresee coming along in the future that has a chance, in the long run, to remain the method to continuously improve the quality and prolong the duration of human life.
We shall never forget that humans obviously cannot change natural laws, but by discovering their mechanisms of action, they learn to make use of this knowledge. By conquering gravitation, man stepped across his naturally given limit and ultimately landed on the moon. By conquering the age-related decline of the mesencephalic enhancer regulation, man might in the future step across also this naturally given limit and extend human life span beyond the TLSh.
Q: What are you currently working on?
Dr. Knoll: My ambition is to develop a more efficient compound than deprenyl for slowing the age-related decay of the mesencephalic enhancer regulation, and to detect the envisioned unknown mesencephalic enhancer substances, expected to be several thousand times more active than PEA or tryptamine. Currently we are trying to clarify in more detail the pharmacological spectrum of BPAP—our newly developed, tryptamine-derived, synthetic mesencephalic enhancer substance.
David Jay Brown is the author of four volumes of interviews with leading-edge thinkers, Mavericks of the Mind, Voices from the Edge, Conversations on the Edge of the Apocalypse, and Mavericks of Medicine. (Mavericks of Medicine will be published by Smart Publications as a book in late 2006.) He is also the author of two science fiction novels, Brainchild and Virus. David holds a master’s degree in psychobiology from New York University, and was responsible for the California-based research in two of British biologist Rupert Sheldrake’s bestselling books on unexplained phenomena in science: Dogs That Know When Their Owners Are Coming Home and The Sense of Being Stared At. To find out more about David’s work visit his award-winning web site: www.mavericksofthemind.com.
Knoll J. The possible mechanisms of action of (-)deprenyl in Parkinson’s disease. J Neural Transm. ;43(3-4):177-98. ↑
Knoll J. The facilitation of dopaminergic activity in the aged brain by (-)deprenyl. A proposal for a strategy to improve the quality of life in senescence. Mech Ageing Dev. 1985 May (13;30(2):109-. ↑
Knoll, I. Miklya, B. Knoll, R. Markó and K. Kelemen. (−)Deprenyl and (−)1-phenyl-2-propylaminopentane, [(−)PPAP], act primarily as potent stimulants of action potential-transmitter release coupling in the catecholaminergic neurons. Life Sci. 58 (1996), pp. 817–827. ↑
Knoll J. Rationale for (-)deprenyl (selegiline) medication in Parkinson’s disease and in prevention of age-related nigral changes. Biomed Pharmacother. 1995;49(4):187-95. ↑
Shoulson I, Oakes D, Fahn S, et al. Impact of sustained deprenyl (selegiline) in levodopa-treated Parkinson’s disease: a randomized placebo-controlled extension of the deprenyl and tocopherol antioxidative therapy of parkinsonism trial. Ann Neurol. 2002 May;51(5):604-12. ↑
Ebadi M, Sharma S, Shavali S, et al. Neuroprotective actions of selegiline. J Neurosci Res. 2002 Feb 1;67(3):285-9. ↑
Ebadi M, Brown-Borg H, Ren J, et al. efficacy of selegiline in neurodegenerative disorders and neurological diseases. Curr Drug Targets. 2006 Nov;7(11):1513-29. ↑
Tsunekawa H, Noda Y, Mouri A, et al. Synergistic effects of selegiline and donepezil on cognitive impairment induced by amyloid beta (25-35). Behav Brain Res. 2008 Jul 19;190(2):224-32. ↑
Thomas T. Monoamine oxidase-B inhibitors in the treatment of Alzheimer’s disease. Neurobiol Aging. 2000 Mar-Apr;21(2):343-8. ↑
Robinson DS, Gilmor ML, Yang Y, et al. Treatment effects of selegiline transdermal system on symptoms of major depressive disorder: a meta-analysis of short-term, placebo-controlled, efficacy trials. Psychopharmacol Bull. 2007;40(3):15-28. ↑
Gelowitz DL, Richardson JS, Wishart TB, et al. Chronic L-deprenyl or L-amphetamine: equal cognitive enhancement, unequal MAO inhibition. Pharmacol Biochem Behav. 1994 Jan;47(1):41-5. ↑
Brandeis R, Sapir M, Kapon Y, et al. Improvement of cognitive function by MAO-B inhibitor L-deprenyl in aged rats. 1: Pharmacol Biochem Behav. 1991 Jun;39(2):297-304. ↑
Murphy KJ, Foley AG, O’connell AW, et al. Chronic exposure of rats to cognition enhancing drugs produces a neuroplastic response identical to that obtained by complex environment rearing. Neuropsychopharmacology. 2006 Jan;31(1):90-100. ↑
Zhu J, Hamm RJ, Reeves TM, et al. Postinjury administration of L-deprenyl improves cognitive function and enhances neuroplasticity after traumatic brain injury. Exp Neurol. 2000 Nov;166(1):136-52. ↑
Sandyk R. AC pulsed electromagnetic fields-induced sexual arousal and penile erections in Parkinson’s disease. Int J Neurosci. 1999 Aug;99(1-4):139-49. ↑
Clayton AH, Campbell BJ, Favit A, et al. Symptoms of sexual dysfunction in patients treated for major depressive disorder: a meta-analysis comparing selegiline transdermal system and placebo using a patient-rated scale. J Clin Psychiatry. 2007 Dec;68(12):1860-6. ↑
Knoll J. Antiaging compounds: (-)deprenyl (selegeline) and (-)1-(benzofuran-2-yl)-2-propylaminopentane, [(-)BPAP], a selective highly potent enhancer of the impulse propagation mediated release of catecholamin. CNS Drug Rev. 2001 Fall;7(3):317-45. ↑
Dalló J, Köles L. Longevity treatment with (-)deprenyl in female rats: effect on copulatory activity and lifespan. Acta Physiol Hung. 1996;84(3):277-8.. ↑
Carrillo MC, Kitani K, Kanai S, et al. The effect of a long term (6 months) treatment with (-)deprenyl on antioxidant enzyme activities in selective brain regions in old female Fischer 344 rats. Biochem Pharmacol. 1994 Apr 20;47(8):1333-8. ↑
Freisleben HJ, Lehr F, Fuchs J. Lifespan of immunosuppressed NMRI-mice is increased by deprenyl. J Neural Transm Suppl. 1994;41:231-6. ↑
Knoll J. Deprenyl (selegiline): the history of its development and pharmacological action. : Acta Neurol Scand Suppl. 1983;95:57-80. ↑
Robinson DS, Amsterdam JD. The selegiline transdermal system in major depressive disorder: a systematic review of safety and tolerability. J Affect Disord. 2008 Jan;105(1-3):15-23. ↑
Amsterdam JD. double-blind, placebo-controlled trial of the safety and efficacy of selegiline transdermal system without dietary restrictions in patients with major depressive disorder. J Clin Psychiatry. 2003 Feb;64(2):208-14. ↑