Parkinson's disease: MPTP and drug-induced Parkinson's
MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)
It has been known for more than 60 years that idiopathic Parkinson's disease (PD) is characterised pathologically by the death of neurones in the substantia nigra area of the brain. While this is not the only feature of the disease, it is the most obvious and this kind of damage has been shown to be present with all clinical findings seen in the disease. It is not known why these cells die in PD, or what it is that causes them to die. An answer may lie in the research being undertaken with the recently described neurotoxin, MPTP. This compound appears to be selectively toxic to the cells in the substantia nigra, and is capable of producing virtually all the signs and symptoms of idiopathic PD.
MPTP was first tested for its possible therapeutic use in 1947, but the primates that were given the drug became rigid and unable to move, eventually dying. The compound was being tested as a possible anti-parkinsonian agent. After 6 humans were given the drug and developed PD symptoms and 2 died, the drug was abandoned.
However, after the production of another compound, MPPP (an illicit narcotic compound), the importance of MPTP to PD was discovered.
The first case of MPTP causing parkinsonism occurred in 1976 when a young college student who manufactured and abused MPPP made a mistake in his synthesis and produced MPTP. Within 3 days he was severely parkinsonian and his family thought he was schizophrenic. Eventually he was placed on and responded to Sinemet. Two years later he committed suicide and the autopsy showed cell destruction in the substantia nigra, and the damage was, in fact, the same as that seen in PD patients.
In 1982 MPPP was again manufactured and sold in the street as synthetic heroin. It was not long before contaminated batches containing MPTP hit the streets, which dealt a devastating blow to the young users. Hospitals began admitting patients as young as 19 with severe end stage parkinsonian symptoms. The source was tracked down to MPTP and its effect was found to be permanent damage to the neurones of the substantia nigra. This left patients with what was clinically idiopathic PD.
Not only do patients with MPTP-induced parkinsonism manifest all the typical features of idiopathic PD, but associated features are present also. These observations have a direct bearing on the anatomical site of the origin of the signs and symptoms in PD.
All the evidence to date suggests that patients with MPTP-induced parkinsonism have lesions limited to the substantia nigra, and exhibit virtually all of the clinical features of this disease. These patients therefore provide powerful support for the argument that most, if not all, of the motor symptoms and signs in PD can be produced by lesions of the substantia nigra.
While patients with MPTP-induced parkinsonism show all the clinical features of PD, it is not PD. As a model it is ideal, but it is a separate disease and it does differ from idiopathic PD. MPTP-induced parkinsonism is very selective, whereas with idiopathic PD other areas of the brain are affected.
MPTP-induced parkinsonism is very rapid in its onset (as quick as a few days to full symptoms), whereas idiopathic PD has a slow progression and may take years to become evident. Another major difference is the presence of Lewy bodies. These are concentric inclusion bodies which can be identified by using a red dye called eosin. They are considered a hallmark of idiopathic PD but are yet to be demonstrated in MPTP-induced parkinsonism.
The major trials with MPTP have been carried out by Dr J. William Langston, who has written a book on MPTP based upon his tests and observations of the drug. He has tested the drug on animals, observed its effects on humans, and provided the medical world and people with PD with a vast amount of valuable information on the effects and consequences of this drug. One of the most important findings of the animal tests is that MPTP can produce severe parkinsonism in monkeys.
If a monkey is treated with oral doses of levodopa, one can observe wide fluctuations in motor function as well as a 'wearing off' period. Since these animals have not been exposed to high doses of levodopa it is this evidence which led Dr Langston to one of his major conclusions: 'The complications which occur with L-dopa therapy, such as dose limiting dyskinesia and 'on-off' phenomena, may be more related to severity of disease than to duration of therapy.' This finding would seem to support the use of early levodopa treatment.
The most fascinating part of the discovery of MPTP is that it has caused scientists to take an interest in finding an environmental cause for the disease. Probably the most astounding case of possible environmental factors is the case of a chemist who contracted PD whilst working with MPTP. The only possible forms of infection were through the skin or by inhaling the vapour. While it may be considered coincidental, several other similar cases have since been reported, making it a possibility that MPTP does not need to be injected to have an effect on the substantia nigra.
The preliminary finding concerning MPTP and its relationship to PD has added another dimension to the study of the disease. Although MPTP is not the cause of idiopathic PD, it does suggest a chemical basis for the disease which may lead to further discoveries in this area, and the possibility of a chemical cure.
Other drugs
Other compounds which induce parkinsonism include phenothiazines (including metoclopramide), butyrophenones and reserpine. The onset of drug-induced parkinsonism is more rapid than that of PD, and the symptoms usually dissipate over a period of several weeks if these drugs are withdrawn.
There have been other reports of drug-induced parkinsonism, especially connected to a group of farmers exposed to a particular chemical spray. The compound MPTP is a pyridine and has a very simple molecular structure. Many chemical sprays contain the MPTP molecule but it is not known why the compound is not harmful when placed in these compounds. Perhaps the other parts of the compound act as an inhibitor to the MPTP. However, because we can isolate the MPTP molecule it makes it a lot easier to find other instances in which MPTP has been used and placed into our environment.
Last Reviewed: 23 July 2002
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