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STOCKHOLM- Natural proteins derived from brain cells may offer a new therapeutic approach to neurodegenerative diseases such as Parkinson's disease, report researchers.

Parkinson's disease results from a loss of cells in the area of the brain called the substantia nigra. This in turn results in a depletion of the neurotransmitter dopamine. While neuroscientists understand something about what is happening in the substantia nigra, very little is known about why it happens.

One hypothesis is that Parkinson's is caused by a lack of sufficient dopaminotrophic support. Researchers at the Karolinska institute in Stockholm conducted a series of experiments in mice using a cloned version of a natural protein associated with nerve cell growth called glial cell line-derived neurotrophic factor (GDNF) to test this hypothesis.

One of the most important events in the history Parkinson's disease research resulted from the unfortunate experience of a handful of drug abusers in the San Francisco bay area. The drug users had appeared at local medical centers with symptoms of Parkinson's disease (tremors etc.) after taking a new designer drug called MPTP. Animal studied showed that the drug had a potent and specific neurotoxic effect on dopamine producing brain cells, leading to the understanding that Parkinson's disease was a problem of dopamine deficiency.

Since that time, MPTP has been used in animal studies to induce Parkinson's-like brain deterioration. The Swedish researchers injected GDNF into the brains of mice and then later injected them with the MPTP toxin. The GDNF injection provided impressive protection from the effects of the toxin. When GDNF was administered after injection of the toxin, much of the destructive effects of the toxin were reversed and dopamine levels restored.

"We conclude that intracerebral GDNF administration exerts both protective and reparative effects on the nigrostriatal dopamine system, which may have implications for the development of new treatment strategies for Parkinson's disease," notes Dr. Lars Olson of the Karolinska Institute

Another group of researchers conducted a similar series of experiments. However, instead of using a neurotoxin to impair dopamine production, they transected axons i the forebrains of rats. Left untreated, the result was a significant loss of dopamine producing neurons in the substantia nigra. However, with repeated injection of GDNF adjacent to the substantia nigra , this neuronal loss was largely prevented.

"Our findings show that GDNF can prevent the degeneration of dopaminergic neurons in the adult mesencephalon, suggesting a potential usage for GDNF in therapeutic approaches to Parkinson's disease. GDNF so far is the only identified factor with highly potent trophic activity on dopaminergic neurons in vivo," noted Dr. Klaus Beck, department of neuroscience, Genentech.

Two other research groups reported that GDNF appeared to protect nerve cells involved with muscle function, suggesting the protein might also prove useful in the treatment of a number of degenerative disorders including Lou Gehrig's disease (amyotrophic lateral sclerosis).

All four of these studies appeared in Nature, v.373, 1/26/95. BACKGROUND

Nearly one million people in the U.S. have Parkinson's disease. This is a mysterious disease with no known cause or cure. The cause of Parkinson's disease is currently thought to be a combination of environmental and genetic factors.

The symptoms of Parkinson's disease were first described by British physician Dr. James Parkinson in 1812. The first symptom is often an involuntary tremor. As the disease progresses, the muscles become stiff and the face loses all expression. Patients also develop difficulty walking and standing.

The first treatment breakthrough came with levadopa. The drug essentially replaces the lost dopamine in the brain. However, large doses are required, resulting in undesirable side effects, such as nausea, heart problems & dementia. The subsequent development of carbidopa, which is given in conjunction with levadopa, allows a smaller dose of levadopa to be used, resulting in fewer side effects.

Many patients respond well at first to this combination therapy, but after a couple years of treatment the effects may begin to wear off. At the same time, prolonged use of levadopa can have serious side effects including involuntary movements of the limbs and psychological disturbances.

A new treatment called seligiline has recently become available which has a completely different mechanism of action from levadopa. The drug is potent inhibitor of an enzyme called 'monoamine oxidase B' which breaks down dopamine. This means more dopamine can be preserved in the brain. The drug appears to have a neuroprotective effect and may delay the onset of Parkinson's symptoms.

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