SPRING Times No. 41, October 2006 Page 15:

By John Telford

Synapses connect nerve cells – so, in a sense, they connect thoughts. In this edition of ST, as in many others, articles written quite separately have born an unexpected relationship with each other. A discussion in one has serendipitously thrown light on another. The thoughts crossing the synapses in this edition relate to oxidative stress, neuroprotection and monoamine oxidase inhibitors such as selegiline

The article by Michael Kelly on exercise in the last edition prompted John Pepper to write in about how he believes regular, strenuous exercise has helped keep his Pd symptoms at bay. He happened to mention in correspondence that he had used selegiline (Eldepryl) as a monotherapy for many years (i.e. without any levodopa). I was not aware that there was any advantage in using selegiline on its own but another of our regular contributors had also used it in this way. But there should be no surprise about this mode of use. Monoamine oxidase type B inhibitors (MAO-b inhibitors) certainly slow down the degradation of the dopamine in the brain that has resulted from levodopa administered, as Pd therapy. But it will of course also extend the life of the dopamine produced naturally by the neurons. Therefore: in the early stages of the disease, when dopamine production has started to decline, an MAO-b inhibitor can help to conserve what dopamine is still being produced by the cells, not yet affected.”

The link between ideas relates to Flora Hill’s article above[1] on alpha synuclein. In the model 2 that she describes, free dopamine is seen as harmful. Not in itself but because of the highly reactive oxygen species which are formed when excess of it is metabolized. The first stage of a major route in the metabolization of dopamine is the action of a monoamine oxidase – the very enzyme that compounds like selegiline act against. (The relatively new drug, rasagiline, which is marketed as Azilect is of the same class.) Model 2, then, suggests that such drugs may help with neuroprotection, by inhibiting the harmful degradation of any dopamine that has escaped being re-absorbed.

So the question is; has selegeline contributed to the slowness of PD progression that John Pepper has experienced? Well, we have to be cautious. One swallow does not make a summer, and conclusions cannot reliably be drawn from anecdotal evidence. After all, there still remains some question of whether John Pepper really has ‘standard’ Pd. Instead, the correct answer is what Flora proposes: that further research is done, firstly, to confirm the results of the trial she quotes, which point to MAO-b inhibitors being neuroprotective and second, to determine whether they are neuroprotective by the mechanism she outlines.

The following information was supplied by the Parkinson’s Post, Published by the Northwest Parkinson’s Foundation[2]:

On May 16, 2006, the Food and Drug Administration (FDA) approved a new drug, rasagiline, for the treatment of Parkinson's disease (PD). Rasagiline, which will be sold under the name of Azilect^® in the United States, is taken once a day. The manufacturer, Teva Pharmaceuticals, intends to have two strengths of this drug available for sale in the US later this year.

The FDA approved rasagiline as a stand-alone treatment for early PD and in combination with levodopa, a commonly used drug to treat PD, for the signs and symptoms of moderate to advanced PD. These approvals were based on the results of three clinical studies.

The first study included 404 participants who had early PD and were not taking any dopamine-like drugs for the treatment of PD. The study lasted for 26 weeks. The results showed that rasagiline was better than placebo at controlling the symptoms of PD, as measured by the Unified Parkinson Disease Rating Scale (UPDRS). The UPDRS is a tool that doctors often use in research studies to measure the effects of PD.

A total of 1,159 people with moderate to severe PD participated in the second two studies. These people were taking levodopa and had motor fluctuations, dyskinesias, or both. They kept a diary at home and recorded the amount of "off" time that they had each day. Both studies found that the addition of rasagiline to the subjects' usual medications reduced the amount of off time, as compared with before they started taking rasagiline. In addition, some people were able to decrease their dose of levodopa.

Additional studies will be conducted to evaluate the impact of dietary tyramine on people taking rasagiline (see the information below on monoamine oxidase (MAO-b inhibitors) and whether taking rasagiline increases a person's risk of developing melanoma. In the studies of rasagiline that have been completed, the rate of melanoma was slightly higher in those taking rasagiline, but it is not clear whether this was due to the drug or happened by chance and was not related to the drug. For now, people taking rasagiline should follow a diet that does not include foods that contain tyramine and should undergo regularly scheduled examinations of their skin to look for melanomas.

Azilect is in a class of drugs known as monoamine oxidase inhibitors (MAOIs). These drugs affect chemicals in the brain known as monoamines--serotonin, dopamine, and norepinephrine. Monoamines are involved in the transmission of messages between nerve cells. Dopamine is particularly important in regulating messages related to movement. People with PD have a decreased amount of dopamine in their brains.

After monoamines perform their jobs as messengers, they are broken down by a type of protein known as an oxidase. Rasagiline, like other MAOIs, limits, or is an inhibitor of oxidation, (which is the process of combining oxygen with some other substance). Because they inhibit oxidation, MAOIs increase the level of monoamines, including dopamine, in the brain.

Unfortunately, MAOIs also inhibit or prevent the breakdown of a naturally occurring substance known as tyramine. When tyramine builds up in the body, it can cause extremely high blood pressure, leading to rupture of blood vessels in the brain or even death. Many prescription and over-the-counter medications, such as antidepressants and cough-and-cold medicines, and dietary supplements contain tyramine or also interfere with the breakdown of tyramine. Therefore, if you are taking rasagiline, make sure that you are aware of these substances and that every healthcare provider who cares for you, including the person administering your anesthesia, if you are having an operation, knows that you are taking an MAOI.

A wide variety of foods also contain tyramine, and the level of tyramine increases in protein-based or processed foods as the protein breaks down. Eating the freshest possible meats and other protein-based foods is very important. Therefore, it's a good idea if you are taking an MAOI, to eat only food that is freshly prepared--let someone else finish off the leftovers, and you may want to steer clear of the buffet line at a restaurant. Some foods should be limited because they contain small amounts of tyramine, and others should be avoided completely. Be sure to check with your doctor for a complete listing of foods and medications that you should avoid. People with liver problems should also not take MAOIs. (Google Tyramine, for more information)

People who take MAOIs should be aware of the symptoms of high levels of tyramine, including severe headache, blurred vision, difficulty thinking, seizures, chest pain, unexplained nausea or vomiting, or signs or symptoms of a stroke. Patients and caregivers should seek immediate medical attention for patients who develop any severe headache or other atypical or unusual symptoms not previously experienced