Aetiology And Prevention

If the symptoms of PD arise when nigra cell loss results in a particular depletion of striatal DA (e.g. 50% or more) and, as is generally assumed, there is a gradual loss of nigra cells during ageing then we should all develop PD if we live long enough. Fortunately this is not the case as many people can reach 90 or 100 years without developing PD. In fact, PM studies show that in normal subjects nigra DA cell loss proceeds at 4-5% per 10 years but in PD sufferers it occurs at almost ten times this level (Fearnley and Lees 1991).

Thus either the gradual loss of nigral cells and striatal DA is accelerated for some reason in certain people, so that these markers fall to below 50% of normal around 5560 years, or some people experience a specific event (or events) during life which acutely reduces DA concentration. This could be to a level which is not enough to produce PD at the time but ensures that when a natural ageing loss of DA is superimposed on it the critical low level will be reached and PD emerge before natural death. The first possibility is likely to have a genetic basis but although examples of familial PD are rare there is typically an increased incidence (2-14) of the disease in the family of a PD patient and initial PET studies show a much higher (53%) loss of DA neuron labelling in the monozygotic than the dizygotic twin of a PD sufferer even if the disorder is not clinically apparent.

While a number of gene markers have been identified in different families there is no consistent mutation although parkin on chromosome 6 and a synuclein on 4 have aroused most interest. Mutations of the gene encoding the latter, such as threonine replacing alanine on amino acid 53 (A53T) or phenylalanine for alanine on 30 (A30P) have certainly been established in particular families with inherited PD. In fact ablation of the gene encoding a synuclein has been shown to produce locomotor defects in mice and surprisingly in the fruitfly Drosophila melanogaster. By expressing normal human a synuclein in all the nerve cells of Drosophila, Feany and Bender (2000) found no neuronal abnormalities but with wild-type a synuclein or the mutants A53T and A30P they observed premature and specific death of dopaminergic neurons. Additionally some neurons showed intracellular aggregates that resembled Lewy bodies and were composed of the a synuclein filaments seen in the human counterpart. Of course, flies cannot be said to develop PD but unlike normal ones, the transengic fly found it more difficult to climb the sides of a vertical vial.

The fact that some schizophrenics show PD symptoms when given DA antagonists has been considered to indicate that they already have a reduced DA function and are asymptomatic potential PD patients but the high incidence of PD side-effects after neuroleptics and its occurrence in young people (20-30 years) argues against this. A viral infection can lead to PD as evidenced by its high incidence (50%) in survivors of an outbreak of encephalitic lethargica in Europe around 1920. Toxins can also be inducers.

In 1982 there was a small outbreak of PD among Californian heroin addicts taking what was thought to be a methadone substitute, but due to a mistake in synthesis turned out to be a piperidine derivative MPTP (1-methyl-4-phenyl-1,2,3,6-tetra hydro-pyridine). By any route, even cutaneous or inspired, this causes a specific degeneration of nigral DA neurons in humans and primates but not in rodents, which may indicate some link with melanin (not found in rodents). MPTP itself is not the active factor but requires deamination by mitochondrial MAOB to a charged pyridium MPP+ which is taken up specifically by DA neurons. MAOB inhibitors such as selegiline prevent MPTP-induced PD in primates. The production of MPP+ generates free radicals as does the oxidation of DA itself.

Free radicals and peroxides are highly reactive substances and can damage DNA, membrane lipid and cell protein and initiate lipid peroxidation to destroy all membranes. Hydrogen peroxide (H2O2) can actually be produced by the oxidation of DA, under the influence of MAOB and is potentially toxic to SN neurons (Fig. 15.11). Normally such H2O2 would be detoxified by glutathione but glutathione activity is low in brain so that H2O2 can accumulate. While a reduction in glutathione itself is not sufficient to destroy nigral cells, since its direct inhibition alone does not have that effect, the rise in H2O2 coupled with its conversion to toxic radicals could do so. This process is also favoured by the high levels of free iron in the substantia nigra which are augmented in PD patients. Iron is normally bound in the body by ferritin but as this is low in the brain the iron will increase and facilitate the production of free radicals. Thus the SN, sitting as it does with high DA levels, ample MAO for converting it to H2O2, little chance to detoxify it but plenty of iron for free radical production, is ready to self-destruct. Whether this is enhanced by dopa therapy and the provision of more DA is uncertain but it has been shown that systemic L-dopa does undergo auto-oxidation in rat striatum to a semiquinone (Serra et al. 2000). This process is inhibited by antioxidants and enhanced by manganese and, of course, miners of this element are known sometimes to develop Parkinsonism-like symptoms and as indicated above, were the first patients to be shown to respond to L-dopa therapy. Whether antioxidants should be given with L-dopa may bear investigation although when one such agent, tocopherol, was tested alone, i.e. on otherwise untreated PD patients, it failed to retard the development of symptoms.

The reliance of free radical and MPP+ production on MAOB activity stimulated considerable interest in the possibility that blocking this enzyme could prevent the


3:4 dihydroxyphenylacetylaldehyde + NH3 +

Continue reading here: Toxification Detoxification

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