Antiaging Compounds: (‐)Deprenyl (Selegiline) and (‐)1‐(Benzofuran‐2‐yl)‐2‐propylaminopentane, [(‐)BPAP], a Selective Highly Potent Enhancer of the Impulse Propagation Mediated Release of Catecholamines and Serotonin in the Brain
Abstract
Hundreds of millions of people now die over the age of 80 years primarily due to twentieth century progress in hygiene, chemotherapy, and immunology. With a longer average lifespan, the need to improve quality of life during the latter decades is more compelling. “Aging — The Epidemic of the New Millenium,” a recent international conference (Monte Carlo, June 17–18, 2000), showed with peculiar clarity that a safe and efficient drug strategy to slow the age‐related decay of brain performance is still missing. This review summarizes the physiologic and pharmacologic arguments in favor of a peculiar lifelong prophylactic medication with reasonable chances to keep in check brain aging and decrease the precipitation of age‐related neurological diseases.
SUMMARY AND CONCLUSIONS
The specific brain activation mechanism (“drive”) that ensures that living beings surmount every obstacle to reach a goal, even if life is in the balance, roots in the existence of “enhancer‐sensitive” neurons in the brain that are ready to increase their activity with lightning speed in response to endogenous “enhancer” substances, of which phenylethylamine (PEA) and tryptamine are the presently known examples. PEA and tryptamine enhance the impulse‐propagation‐mediated release of catecholamines and serotonin in the brain (CAE/SAE effect). This is the best model for studying the enhancer regulation in the mammalian brain, which starts working at the discontinuation of breast feeding. Weaning is the beginning of the developmental (“uphill”) period of life and is characterized by significantly higher brain activity levels that last until the sexual hormones dampen this regulation, thereby terminating the uphill period. This is the prelude of the postdevelopmental (“downhill”) phase of life and the beginning of the slow brain aging process from which there is no escape until natural death.
It has been proposed that enhancer compounds can delay the natural age‐related deterioration of brain performance and keep the brain on a higher activity level during postdevelopment longevity. PEA, a substrate of MAO‐B, and tryptamine, a substrate of MAO‐A, are rapidly metabolized, short‐acting endogenous enhancer compounds. PEA and its long‐acting derivatives, amphetamine and methamphetamine, which are not metabolized by MAO, are enhancer substances at low concentrations but also potent releasers of catecholamines and serotonin from their pools at higher concentrations. The catecholamine‐releasing effect masked for decades the enhancer property of these compounds.
(‐)Deprenyl (selegiline) is the first PEA derivative free of the catecholamine‐releasing property and made possible the discovery of the enhancer regulation in the brain. This drug is presently the only clinically used enhancer compound. (‐)Deprenyl is also a highly potent, selective inhibitor of MAO‐B and is metabolized to amphetamines. Tryptamine is an endogenous enhancer substance free of the catecholamine/serotonin‐releasing property. The newly developed tryptamine derivative (‐)BPAP is the first highly selective enhancer substance. It is also much more potent than (‐)deprenyl.
Enhancer substances that keep the enhancer‐sensitive neurons on a higher activity level slow the age‐related deterioration of the mammalian brain. Maintenance of rats on (‐)deprenyl during post‐developmental longevity slows the age‐related decline of sexual and learning performances and prolongs life significantly. Patients with early Parkinson’s disease who are maintained on (‐)deprenyl need levodopa significantly later than their placebo‐treated peers and they live significantly longer when on levodopa plus (‐)deprenyl than patients on levodopa alone. In patients with moderately severe impairment from Alzheimer’s disease, treatment with (‐)deprenyl slows the progression of the disease.
(‐)BPAP is an especially promising prophylactic antiaging compound that may provide the opportunity to shift the functional constellation of the brain during postdevelopmental longevity towards the one characteristic to the uphill period of life. According to the available experimental and clinical data, it is reasonable to expect that daily administration of an enhancer drug [e.g., (‐)deprenyl 1 mg or (‐)BPAP 0.1 mg] from sexual maturity until death will improve quality of life in the latter decades, shift the time of natural death, decrease the precipitation of age‐related depression, and reduce the prevalence of Parkinson’s disease and Alzheimer’s disease.
Keywords: Selegiline, Deprenyl, Antiaging drugs, BPAP
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Selected References
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