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Deprenyl: A Universal Anti-Aging Strategy?

by Ward Dean, M.D., and Steven Wm. Fowkes

The precipitous decline of dopamine-containing neurons in the human brain after age 45 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 who's brain nigrostriatal regions age prematurely develop symptoms of Parkinson's 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.

Unique Pharmacology of Deprenyl

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.

Variable Aging in the Brain

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 Parkinson's disease. Those with normal or slow decline (see illustration) die before Parkinson symptoms become apparent.

This model of nigrostriatal aging and the development of Parkinson's disease has been advanced by Dr. Jozsef Knoll, the world's 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.

Deprenyl and Antioxidant Defenses

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.

Life Extension and Cognitive Enhancement

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.

Conclusion

Deprenyl's 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 Parkinson's disease and is currently being established as a treatment for Alzheimer's disease. Eventually, deprenyl may become recognized as a general treatment for aging in the above-45-year-old population.

References:

Knoll J, (-)Deprenyl-medication: A strategy to modulate the age-related decline of the striatal dopaminergic system. J Am Geriatr Soc 40(8): 839-47, August 1992.
Knoll J, The pharmacology of selegiline ((-)deprenyl). New aspects. Acta Neurol Scand 126: 83-91, 1989.
Carillo MC, Kanai S, Nohubo M, et al., (-)Deprenyl induced activities of both superoxide dismutase and catalase in young male rats. Life Sci 48: 517, 1991.
Knoll J, The possible mechanism of action of (-)deprenyl in Parkinson's disease. Journal of Neural Transmission 43: 239-44, 1978.
Knoll J, Yen TT and Dallo J, Long-lasting, true aphrodisiac effect of (-)deprenyl in sluggish old male rats. Mod Probl Pharmacopsychiat 19: 135-53, 1983.
Sunderland T et al., Tyramine pressor sensitivity changes during deprenyl treatment. Psychopharmacology 1985.
Tariot PN et al., L-Deprenyl in Alzheimer's Disease: Preliminary evidence for behavioral change with monoamine oxidase B inhibition. Archives of General Psychiatry 44: 427-33, May 1987.
Martini E et al., Pharmacopsychiatry 20: 256, 1987.
Knoll J, The striatal dopamine dependency of life span in male rats. Longevity study with (-)deprenyl. Mechanisms of Ageing and Development 46: 237-62, 1988.
Knoll J, Extension of life span of rats by long-term (-)deprenyl treatment. Mount Sinai J Med 55: 67-74, 1988.
The Parkinson Study Group, Effect of deprenyl on the progression of disability in early Parkinson's disease. The New England Journal of Medicine 321: 1364-71, 16 November 1989.
Letters to the Editor on deprenyl in Parkinson's disease, The New England Journal of Medicine 322: 1526-7, 24 May 1990.
Milgram NW et al., Maintenance on L-deprenyl prolongs life in aged male rats. Life Sciences 47: 415-20, 1990.

Report: Vitamin E, Deprenyl slow Alzheimer's disease

Report: Vitamin E, Parkinson's drug slow Alzheimer's disease April 23, 1997
Web posted at: 11:35 p.m. EDT

WASHINGTON (CNN) -- Researchers said Wednesday that Vitamin E and a drug used to treat Parkinson's disease may slow the deterioration caused by Alzheimer's disease.

"I think it's a big deal for two reasons," Mary Sano of Columbia University's College of Physicians and Surgeons said at a news conference.

"These are outcomes that relate to the quality of life of patients and their families ... The second reason is because it's important to do these kinds of ... long studies and look at meaningful outcomes."

The findings, reported in Wednesday's New England Journal of Medicine, show that patients who took vitamin E or the anti-Parkinson's drug selegiline or eldepryl were able to delay for six to seven months key symptoms of the disease, such as memory loss and the ability to bathe and dress.

"We believe that the results of this study will be used to change the prescribing practices in the United States and probably many other parts of the world," Dr. Leon Thal of the University of California at San Diego said.

Sano led a team that followed 341 patients with moderately severe Alzheimer's symptoms over two years. The patients were divided into groups that were treated with a placebo, Deprenyl (selegiline), vitamin E and a combination of the two drugs.

The placebo group lagged behind the other three. Those other three groups were statistically similar in slowing the effects of Alzheimer's, the researchers said. The combination group did not show a notable advantage, they found.

Edward Truschke, president of the Alzheimer's Association, which provides support and research money to combat the disease, hailed the study's results.

"We are very excited that the study showed not only that the clinical signs of disease progression can be slowed but also that, for the first time, drugs were effective with people in the moderately severe stages of the disease."

The researchers recommend that patients with moderately severe Alzheimer's take either high doses of vitamin E -- about 2,000 international units per day, or selegiline. But don't take a combination of the two, they advised, because it's less effective.

Both Depreny and high doses of vitamin E carry potential problems. Deprenyl should not be taken with certain antidepressants and narcotics, and vitamin E may increase the risk of bleeding in some people, the researchers said.

But of the two, vitamin E is cheaper, doesn't require a prescription and presents fewer complications It's not clear how vitamin E and deprenyl work, although it's suspected they slow the progression of Alzheimer's by preventing oxidative damage of brain cells.

Other drugs such as tacrine have been shown to slightly improve memory and thinking in Alzheimer's patients.

Vitamin E and deprenyl may allow patients with moderately severe Alzheimer's to take care of themselves longer, thus relieving some of the burden on their families.

These statements have not been evaluated by the Food and Drug Administration. These products are not intended to diagnose, treat, cure or prevent any disease.