This is a most impressive work, a tour de force, by one of the pioneers of neuropsychopharmacology. It documents Joseph Knoll’s research over six decades that led to the development of the first drug that could prolong longevity in several species of animals.
The story begins in the 1950s in the laboratories of the pharmacology department, Medical University of Budapest, where Knoll, while still a medical student, develops a methodology for the study of “acquired drives” (conditional reflexes) in rats.
Knoll’s research continued in the 1960s with structure-activity studies of centrally acting stimulant drugs, in the course of which he discovered that one of the long-acting phenylethylamine derivatives, (-)-deprenyl, a substance with monoamine oxidase (MAO) inhibiting property, differed from all other MAO inhibitors available at the time by inhibiting the effects of tyramine. The discovery led to the introduction of (-)-deprenyl, referred to also as selegiline, into the treatment of depression as the first MAO-inhibitor without the cheese effect.
Instrumental to further development was Knoll’s demonstration in 1970 that selegiline differed also from all other MAOIs available at the time by selectively inhibiting MAO-B, the enzyme involved in the oxidative deamination of dopamine. It led to the extension of selegiline’s indications to Parkinsonism.
The turning point in Knoll’s research with selegiline was his discovery in the 1980s that the drug enhanced catecholaminergic activity in doses much below that required for MAO inhibition. Important also was his demonstration that the age related decrease of dopamine content in the striatum and decline in sexual activity could be delayed by preventive treatment with the drug. These findings opened up the line of research that led to the demonstration that selegiline could prolong longevity in several species of animals by slowing “brain aging”, as shown by the decrease in some age related changes, e.g., accumulation of lipofuscin in brain cells.
The finding that some of the clinical effects of selegiline can be attributed to the enhancement of catecholaminergic activity, also opened up a new area of research in neuropharmacology: the screening for “enhancer” substances. One of the major contributions of this new area of research is Knoll’s discovery of (-)-BPAP, a tryptamine derived enhancer of both serotonergic and catecholaminergic activity.
Knoll, a vigorous octogenarian, who has himself taken deprenyl for the past twenty years, is still fully active in his research. He is one of the last giants of a bygone era in pharmacology whose research was guided by theories. By using his theory of “enhancer regulation”, as framework for presenting experiments conducted over years, Knoll makes it possible for readers to follow not only his findings but also his thinking. One wonders if he had operated without his theory whether some of the potential benefits of selegiline would have remained hidden.
Thomas A. Ban
Emeritus Professor of Psychiatry
Deprenyl, developed in the early 1960s with the aim to combine the psychostimulant effect of PEA with the psychoenergetic effect of the MAO inhibitors, became world-wide known and used as the first selective inhibitor of B-type MAO, which did not block the activity of the intestinal A-type MAO, thus was free from the cheese-effect.
Further studies revealed that in low doses, which leave MAO activity unchanged, deprenyl is enhancing, via a previously unknown mechanism, the activity of the catecholaminergic neurons in the brain stem and this catecholaminergic activity enhancer (CAE) effect is the primarily important pharmacological effect of deprenyl.
The main aim of this book, which recapitulates a part of information included in my previously published monograph „The Brain and Its Self” (Springer, 2005), is to focus attention to the theoretical and practical importance to the enhancer-regulation in the brain. It summarizes experimental and clinical data in support to the proposal that the prophylactic administration of a CAE substance during postdevelopmental life could significantly slow the aging-related decay of behavioral performances, prolong life, and prevent or delay the onset of aging-related neurodegenerative diseases such as Parkinson’s and Alzheimer’s.E-250, later named deprenyl, was one of the newly synthetized compounds in a structure-activity-relationship study which we performed in the early 1960s with the aim to combine the psychostimulant effect of PEA with the psychoenergetic effect of the MAO inhibitors.
There is no conflict of interest regarding the data in this book
Department of Pharmacology and Pharmacotherapy
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