Posted 02 July 2004 - 01:30 AM
DEPRENYL MAO-B INHIBITOR EXTRAORDINAIRE
By 1971 Knoll had shown that DPR was a unique kind of MAO inhibitor - a selective MAO-B inhibitor, without the cheese effect. To fully appreciate what this means, some technical background is necessary.
Some of the most important neurotransmitters in the brain are the monoamine (MA) transmitters: serotonin, dopamine and noradrenalin. After being secreted into the synaptic gap, where one neuron connects to another, many to the transmitter molecules are reabsorbed by the secreting neuron and then disposed of by enzymes called monoamine oxidases (MAO). This prevents excessive levels of transmitters from accumulating in the synaptic gap and over-amping the brain. However, with aging MAO activity significantly increases in the human brain, often to the point of severely depressing necessary levels of MA transmitters. (1) In the 1950s the first antidepressant drugs to be developed were MAO inhibitors (MAOI). By the 1960s however, MAOIs began to drop out of medical use due to a dangerous side-effect - the so-called cheese effect. When most MOIs are used in people consuming a diet rich in a substance called tyramine, a dangerous, even fatal, high blood pressure crisis can be triggered. Tyramine is found in many foods, including aged cheeses, some wines, beans, yeast products, chicken liver and pickled herring, to name just a few. (23)
By 1968, further research had shown that there were two types of MAO-A and B. It is primarily intestinal MAO-A that digests incoming tyramine. Most of the MAOIs that have been used clinically inhibit both MAO-A and MAO-B, thus setting up the danger of the cheese effect by inhibiting intestinal and brain MAO-A, allowing toxic tyramine levels to accumulate. DPR is unique among clinically used MAO-Is. At normally used clinical dosages (10-15 mg/day), DPR is a selective MAO-B inhibitor, so it doesnt prevent intestinal MAO-A from digesting dietary tyramine.(1) In addition, DPR has the unique ability to prevent tyramine from getting into noradrenalin-using nerve calls, and its only when tyramine enters noradrenalin nerve cells that control arterial blood pressure that it triggers the cheese effect. (1) DPR thus has a dual safety lock in preventing the cheese effect, making it far safer than other MAOIs. At doses over 20-30 mg/day, however, DPR does start to significantly inhibit MAO-A , so there is some risk of the cheese effect at these higher (rarely clinically used) doses. (1)
MAO-A enzymes break down serotonin (5-HT) and noradrenalin (NA), and to a lesser extent dopamine (DA). MAO-B breaks down DA and the traceamine phenylethylamine (PEA). At doses of 5-10 mg per day DPR will inhibit MAO-B about 90%. (1) It was initially presumed that DPR would increase synaptic levels of DA in DA-using neurons, and this lead to its use to treat Parkinsons disease in the late 1970s, Alzheimers disease in the 1980s-90s, and depression starting in the late 1970s. In his 1983 paper on the history of DPRs clinical benefits to its unique MAO-B effects. (1)
Yet many experts have questioned whether DPRs MAO-B inhibition can significantly increase synaptic DA levels. (14,15) This is due to the fact that MAO-B is found only in glial cells in the human brain, non-nerve cells that support, surround and feed the brains billions of neurons. (1) And whether there is any exchange of DA between these glial cells and the DA-using neurons is still an unanswered question. It is commonly believed that it is MAO-A in DA neurons that breaks DA down. By the 1990s Knoll believed he had discovered the real basis of DPRs being a MAO-B inhibitor. (2)
Yet as will be made clear shortly, even if DPRs originally hypothesized mode of action - directly increasing synaptic DA levels through MAO-B inhibition - is false, DPRs MAO-B inhibition still provides part of its benefit.
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