| SELEGILINE (DEPRENYL) Source: medical-library.net Selegiline (a.k.a. 1-deprenyl) is a drug used as an adjunct in the therapy of Parkinson's disease. Due to its anti-neurodegenerative properties it is biochemically defined as a selective monoamine oxidase type B (MAO-B) inhibitor. Selegiline was originally developed as an antidepressant. To date Selegiline has been medically approved by regulatory agencies for use only in treatment of Parkinson's disease. However recent testing indicates that Selegiline may have some effect on increasing sexual response in aging animals, an observed retardation of normal age dependent deterioration of renal function and of cognitive abilities, including spatial learning ability. Dopamine The physiological working of the brain is carried out by neurotransmitters, one of which is dopamine. It is the premature degradation of dopamine that results in the symptoms of Parkinson's disease. Dopamine is an essential chemical that occurs in many parts of the body. But its highest concentration is in the region of the brain called the basal ganglia, a mass of gray matter in the base of the brain important in movement. The basal ganglia includes a striped organ called the "corpus striatum" and another "nucleus" called the "substantia nigra." The cells of the "substantia nigra," produce dopamine which works its way through the motor pathways of the brain. One of these pathways, leading to the "corpus striatum," is thought to be particularly vulnerable to the damage that leads to Parkinson's disease. The main roles of dopamine in the corpus striatum is the continuous inhibition of acetylcholine release in the caudate nucleus. Dopamine acts as a messenger. If we were to isolate two dopaminergic neurons, the first would communicate with the second by emitting dopamine. Some dopamine thus released would be absorbed by the receiving neuron; some would be lost to metabolism during the journey, and some would be recovered by the sending neuron. This last process is called "re-uptake." This system of synthesis, use and inactivation is necessary to maintain the correct amount of dopamine. In the presence of too much or too little dopamine the brain cannot function optimally. As dopaminergic cells decay, control over movement is diminished. The average person starts to lose dopamine at about age 35, and thereafter the normal supply of this chemical transmitter diminishes by about 13 percent each decade thereafter. Therefore, if a lack of dopamine is the cause of Parkinson's disease, then replacement of the dopamine might possibly remove or relieve the symptoms of the disease. While dopamine plays an important role in those parts of the brain known to control motor function, it also travels to other parts of the brain including the limbic system which affects emotions, and to the cortex, where it may affect memory, intellect and personality. We know this highly branched dopaminergic system to be the source of our active reflexes and our inner drives. Selegiline, because it protects the section of the brain that produces dopamine, may have a protective effect on the decay of the brain brought on by dopamine deficiency. Selegiline as a Selective Monoamine Oxidase Inhibitor Monoamine oxidase is an enzyme which accelerates the breakdown of dopamine. Of all the thousands of enzymes in the body, monoamine oxidase is the most common and the one that has most captured the curiosity and fascination of scientists. Monoamine oxidase is everywhere in the body: the liver, the stomach, the intestines, and other organs. In 1973 it was discovered that monoamine oxidase also ocurred in the brain. In the liver one of the functions of monoamine oxidase is to inactivate a substance called tyramine and to transform it into harmless acetic acid. Otherwise, tyramine can cause a dangerous increase in blood pressure. As we age monoamine oxidase becomes increasingly active leading to depressed levels of neurotransmitters. There are two types of monoamine oxidase, designated MAO-A and MAO-B. Selegiline inhibits only the MAO-B (the one whose activity is centered in the brain). A combination of an ordinary MAO inhibitor with any food containing high amounts of tyramine can result in high blood pressure, with symptoms of stiff neck, nausea, headache, and palpitation. Hypertensive crises have on rare occasions resulted in hemorrhage, strokes or cardiac failure. The collection of side effects caused by ordinary MAO inhibitors are known as the "cheese effect" because tyramine is particularly abundant in aged cheese. It is also present in other dietary foods, including broad beans, yeast extracts, chicken liver, pickled herring, chocolate, red wines, and beer. After several tests to determine the effects on tyramine of four MAO inhibitors used widely in the treatment of depression, all potentiated the harmful effects of tyramine, but Selegiline behaves in a different manner. It was the first MAO inhibitor shown to not inhibit the breakdown of tyramine. Elsewhere in the body, unlike all other MAO inhibitors, Selegiline behaves in a harmless fashion. It causes no damage to the liver and people can tolerate relatively large doses of tyramine after taking Selegiline. Employing an intravenous steady state tyramine infusion technique, the effects of different doses of Selegiline have been studied. The data suggest that Selegiline acts as a selective MAO-B inhibitor at low dosages, but that this selectivity is lost at higher doses (40 - 50 mg), resulting in a significant crossover inhibition of MAO-A and an increased tyramine induced hypertension. The inference is that substantial amounts of tyramine, considerably larger than those likely to be encountered in a diet containing even the most generous quantities of cheese, can be safely consumed by people taking moderate doses of Selegiline. Selegiline possesses the quality of selectivity, blocking only the enzyme which destroys dopamine and allows the breakdown of other monoamines, such as tyramine, to continue. Selegiline is therefore free of restricting "cheese effects," yet is able to increase brain dopamine by preventing its normal breakdown within nerve cells and in the gaps between nerve fibers. As a result it can be used safely with L-dopa and dietary restrictions are unnecessary under 40 mg. Selegiline can enhance the action of small doses of L-dopa given medicinally. More importantly, in patients experiencing a wearing-off effect from each dose of L-dopa, the addition of Selegiline may prolong the duration of benefit. Selegiline has the advantage that it is easy to use and its unwanted effects are few. Therefore, because MAO-A in the digestive tract is not inhibited, patients treated with Selegiline at doses of 10 mg. per day can take medications containing pharmacologically active amines and consume tyramine containing foods without the risk of uncontrolled hypertension. Selegiline in the Aging Brain Alzheimer and Parkinson are both neurodegenerative diseases. Several studies have been conducted to demonstrate the effects of Selegiline on Alzheimer's. Selegiline, by improving the tone of the dopaminergic system, may be useful in treating other neurodegenerative diseases, such as Alzheimer's disease (AD). AD seems to be the result of brain damage in regions removed from the dopaminergic system. Slowing the progression of a degenerative disease would itself tend to prolong life. In the aging brain there is a loss of neurons compensated for by a proliferation of glial cells. Because of the increased MAO-B activity present in the ganglia, neurotransmitter levels drop and thus their modulation in the brain declines with age. Increase in depression in the elderly, age-dependent decline in male sexual vigor and the frequent appearance of Parkinsonian symptoms in the latter decades of life may be due to a decrease of dopamine and trace amines in the brain. This situation can possibly be at least partially alleviated by Selegiline. Oxygen is essential for animal life, but unbalanced oxidative processes within nerve cells may account for dopamine producing cell loss and the eventual signs of Parkinson's disease. It has been shown that the inactivation of dopamine by a process of oxidation results in the formation of free radicals. Such free radicals are capable of cellular damage. Whatever the toxic substance which triggers the production of free radicals, it is the oxidative mechanisms that predispose some people to the loss of dopamine cells. Obviously, therefore, the life-time (or at least from age 35 on) intake of antioxidants has a rational in anti-aging medicine. |