Tackling the Side Effects of Parkinson’s Treatment

Parkinson’s disease is a slowly developing progressive disorder which is estimated to be the second most common neurodegenerative disease. At present, the disease affects 5 million people and the numbers are projected to reach 9 million by the year 2030.

The condition is characterized by the shaking of legs and arms, rigidity, and loss of postural reflexes. Those symptoms are the result of an imbalance between two signalling substances in the brain: dopamine and acetylcholine. In Parkinson’s disease, dopamine is either reduced or lesser effective than normal. This leads to overrunning the brain by acetylcholine which is responsible for the tremors (shaking/trembling) and rigidity. This problem is generally the result of destruction of dopaminergic neurons.

Although we don’t know how to reverse the process of neuron degeneration, we can use a number of treatments to relieve patients’ symptoms and enhance their quality of life.

Treating Parkinson’s disease is primarily a question of restoring a defective balance between brain chemicals. To achieve this goal, we can either support dopaminergic action or reduce the acetylcholine effects. Therefore the actual anti-Parkinson drugs can be classified into two major groups:

• Dopaminergics, which are medicines used to potentiate the dopamine action, and
• Anti-muscarinics, which are used to slow down the cholinergic system and reduce its central effects.

Levodopa is a major drug associated with a number of side effects

The discovery of the mechanism of Parkinson’s in the 1960s led to the great idea of a compensation treatment. The first aim of this approach was to restore the dopamine level in the brain by supplying it through medications. Unfortunately, the dopamine turned out to be unable to pass through the blood-brain barrier.

However, levodopa (commonly named L-Dopa), which is a chemical precursor of dopamine, can enter the brain through a special transporter. Once there, levodopa can be transformed into dopamine. This mechanism made levodopa one of the most important medicines in the treatment of Parkinson’s disease.

Nevertheless, levodopa is subject to an inactivation by specialized enzymes even before reaching the brain. In fact, some enzymes such as monoamino oxidase (MAO) and catechol-O-methyl transferase (COMT) are capable of degrading levodopa, dopamine and other brain chemicals to eliminate them once they have fulfilled their duties. This process of catabolism significantly reduces the amount of levodopa available to the brain.

To resolve the problem, two strategies were developed. The first one is to increase the total levodopa dose and the second one is to prescribe inhibitors for catabolizing enzymes. Once inhibited outside the brain, such enzymes can no longer degrade L-dopa making the substance more available to the brain.

An additional important consideration is the side effects of levodopa. Without the use of enzyme blockers, the drug’s side effects show up quickly. Levodopa can induce a number of side effects such as gastro-intestinal problems, arterial hypotension and cardiac rhythm troubles. In addition, abnormal movements and psychiatric disorders can show up with increased doses of L-dopa.

In the long run, after a “honeymoon” period, a loss of drug’s efficacy in treating the symptoms of Parkinson’s disease is the most feared consequence. This may result in an uncontrollable rigidity and movement problems when levodopa is used alone. As a consequence, increased amounts of the substance are needed which increasingly expose patient to side effect.

Other treatments for Parkinson’s disease

Over the last few decades, a number of other substances have been developed with the objective of supporting the dopaminergic system. Such substances have been named dopaminergic agonists and were designed to mimic dopamine action by interacting with their dopamine receptors and fooling the brain that the needed substance is there. Dopaminergic agonists can be associated with levodopa to increase its efficacy.

The second group of anti-Parkinson drugs is the anti-muscarinics which work by decreasing the excessive release of acetylcholine. Until 1966, they were the only available medicines to treat Parkinson’s symptoms. They are primary used to reduce shaking through blocking acetylcholine action in the brain.

In addition to pharmacological therapies, surgery is also used as a means to control severe and resistant Parkinson’s disease. In such cases, microscopic brain surgery, in which specific neurons are destroyed, can be used to alleviate patient symptoms. A less aggressive technique is deep brain stimulation, which has proved to be effective in treating advanced disease states.

Promising new developments

In parallel to the conventional techniques of treating Parkinson’s disease, there is a number of experimental therapeutics that hopefully might one day lead to a cure for this disabling condition. One solution consists of injecting stem cells that are able to transform into fully functional neurons. Until now, this so-called cell replacement therapy is under intense investigation in a number of clinical trials. The initial results appear to be encouraging, with patients receiving the cells showing some movement improvement with a persistent increase of brain dopamine.

In another study, an international team of scientists approached the problem differently. Rather than search for new methods to treat Parkinson’s disease, they decided to improve what we already have. In their attempt to further understand the interactions between neurons in Parkinson’s affected brains, they discovered that some receptors (the type 4 muscarinics receptors) are able to diminish motor side effects of levodopa, once they are stimulated by the right substance. Although the study was done on animals, it represents a promising strategy to address the levodopa side effect problem.

Other scientists are now trying to re-use some medicines initially prescribed to treat other conditions to find out if Parkinson’s patients can benefit from them. This method is called drug repurposing and is increasingly used to identify some cures for diseases other than the one initially created for.

A totally different strategy is now focusing on preventing, or at least delaying, the disease in the first place. A number of studies showed that protecting neurons from environmental harmful substances by using anti-oxidants can slightly delay the symptoms onset and even bring some moderate improvement.

While the current therapies for Parkinson’s diseases are still symptomatic, new approaches and treatments may help in addressing the problem of side effects, thus greatly improving the quality of life of patients affected by this condition.

References

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