How Selegiline ((-)-Deprenyl) Slows Brain Aging

This e-book is a reference on Selegiline/(-)-Deprenyl effects on the brain. Selegiline, described in thousands of research papers, is registered in over 60 countries. At present, more than one hundred preparations containing selegiline circulate in the global market under different brand names. They are widely used in the treatment of Parkinson’s disease, Alzheimer’s disease, major depression and as a geroptotective / anti-aging drug.

(-)-Deprenyl/selegiline, the first selective inhibitor of B-type MAO which, in contrast to the known MAO inhibitors, did not potentiate the effect of tyramine but inhibited it. The compound could be combined with levodopa in Parkinson’s disease without signs of hypertensive reactions. The DATATOP study in the USA revealed that (-)-deprenyl delayed the onset of disability associated with early, otherwise untreated Parkinson’s disease. The age-related decay of the supply of the brain with phenylethylamine ( PEA), due to the progressive increase of MAO-B activity in the aging brain, and dopamine, due to the better than average decline of the dopaminergic neuronal activity during the postdevelopmental phase of life, are irresistible biochemical lesions of aging. The speed of deterioration of behavioral performances with the passing of time and longevity depends significantly on the pace of the worsening of these leasions. (-)-Deprenyl, Increasing the supply of the brain with PEA and dopamine, counteracts this aging process. Maintenance of male rats from sexual maturity until death on (-)-deprenyl delays the age-related loss of the capacity to ejaculate, slows the age-related decline of learning ability and prolongs life. In humans, maintenance from sexual maturity on (-)-deprenyl (1 mg daily) is, for the time being, the most promising prophylactic treatment to fight against the age-related decay of behavioral performances, prolonging life, and preventing or delaying the onset of age-related neurodegenerative diseases such as Parkinson’s and Alzheimer’s.

This e-book is a useful reference for graduate medical students, academic researchers in the field of neuropsychopharmacology, neurophysiology and gerontology and professional research groups in commercial organizations manufacturing selegiline preparations.

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
Vanderbilt University
USA