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From the August 1992 issue of Smart Drug News [v1n6]. Copyright (c) 1992, 2000. All rights reserved.
Smart Drug Update:
by Ward Dean, M.D., and Steven Wm. Fowkes
The precipitous declindopamine-containing neurons in the human brain after age 45 e of is a universal characteristic of the aging process. The nigrostriatal region of the brain is richest in dopamine and undergoes the most rapid aging of any brain area. People whos brain nigrostriatal regions age prematurely develop symptoms of Parkinsons disease, formerly called the shaking palsy. Age-associated depletion of dopamine also accounts for less noticeable symptoms, like decline in drives, most notably male sex drive.
Deprenyl (selegiline) provides selective protection against the age-related degeneration of the dopaminergic nervous system. It protects sensitive dopamine-containing neurons from the age-associated increases in glial cells (non-neuron brain cells) and the monoamine oxidase (type B) that they contain. Deprenyl is the first selective inhibitor of MAO-B ever discovered, it is the only one used in clinical practice, and it remains the scientific reference standard for B-type inhibition after more than 40 years.
Deprenyl also competitively inhibits the uptake of dopamine, norepinephrine and epinephrine (collectively referred to as catecholamines) into neurons. This unique ability among the MAO inhibitors prevents the cheese effect, a dangerous hypertensive reaction caused by neural uptake of tyramine from tyramine-containing foods like aged cheeses, certain wines, yeast, beans, chicken liver and herring. Deprenyl exhibits no significant cheese effect at therapeutic dosages, and only minimal effects at extremely high dosages.
The rate at which dopamine neurons age is apparently quite variable. Prior to age 45, dopamine levels remain fairly stable. Starting at age 45, average dopamine content in healthy individuals decreases linearly 13% per decade (see illustration 1). When it reaches approximately 30%, Parkinson symptoms result (gray area). Below 10%, death results. Although the average decrease in dopamine is 13% per decade, some individuals exhibit more rapid decline and others less rapid decline. People experiencing rapid dopamine decline manifest with Parkinsons disease. Those with normal or slow decline (see illustration) die before Parkinson symptoms become apparent.
This model of nigrostriatal aging and the development of Parkinsons disease has been advanced by Dr. Jozsef Knoll, the worlds most prominent deprenyl researcher. He suggests that Parkinsonism may be a generic condition of the human species that does not currently manifest in very many people because of our limited average lifespan. He also suggests a general strategy of long-term deprenyl use for the prevention of nigrostriatal aging in the above-45-year-old population.
The sensitivity of the dopaminergic nervous system to oxidizing free radicals is well established. Oxidative polymerization of aromatic amino acids (e.g., phenylalanine, tyrosine, dopa, tryptophan) and aromatic monoamine neurotransmitters (e.g., norepinephrine, epinephrine, dopamine and serotonin) lead to the formation of melanin, a black pigment which is a characterizing feature of the nigrostriatal (black-striped) neurons. Chronic deprenyl treatment lessens the rate of melanin production.
Two oxidized derivatives of dopa and dopamine (6-hydroxydopa and 6-hydroxydopamine, respectively) are potent neurotoxins. The protective effect of deprenyl in lessening the neurotoxic effect of these two chemicals appears to correlate with increased antioxidant enzyme levels, superoxide dismutase (SOD) [Knoll, 1989] and catalase [Carrillo, 1991]. The increase in antioxidant enzymes is proportional to the amount of deprenyl given. The protective influence of deprenyl is selective for dopaminergic neurons; increased SOD is not noted throughout the rest of the brain.
Although the long-term use of deprenyl in normal people as a life-extension and cognitive-enhancing drug has yet to be definitively studied, animal research is extensive. Age-associated decrease in sexual performance and hunger drive in rodents (a dopaminergic function) is dramatically inhibited.
The lifespan studies of deprenyl in rodents is equally dramatic
(see illustration 2); all of the control rats die before the first
deprenyl-treated rat dies.
The life-extending influence of deprenyl is not mediated through a food-restriction mechanism. Deprenyl-treated animals maintain body weight better than control animals.
Early research with deprenyl in humans (early diagnosed Parkinson patients) shows delayed development of symptoms and delayed need for L-dopa therapy. In combination with other drugs, deprenyl has significantly prolonged the survival of Parkinson patients.
Deprenyls low level of toxicity, few side-effects, and unique spectrum of pharmacological activities make it ideal for prophylaxis against nigrostriatal aging and the secondary aging symptoms accompanying the decline of the dopaminergic nervous system. Deprenyl is a drug of choice for Parkinsons disease and is currently being established as a treatment for Alzheimers disease. Eventually, deprenyl may become recognized as a general treatment for aging in the above-45-year-old population.
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