The Parkinson's-Reversing Breakthrough

Medication for Parkinsons

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Figure 13.1. Neurobiological diseases in which Parkinsonian symptoms occur.

Figure 13.2. Section through the brain showing the location of the areas of the basal ganglia that are dysfunctional in Parkinson's disease.

cause a syndrome in man and primates which is indistinguishable from true Parkinsonism. This experimentally induced form of the disease responds to anti-parkinsonian therapy and has been of considerable importance in the development of a useful animal model of the disease. It has been speculated that substances that are structurally related to MPTP may occur in the environment (e.g. some herbicides can produce such compounds), and the possibility arises that repeated exposure to small quantities of such toxins, combined with the effects of ageing, may be sufficient to cause the disease.

While there is little evidence to suggest that endogenous excitotoxic mechanisms play a role in the neuronal degeneration found in parkinson-ism, there is experimental evidence that the excitotoxic action of methamphetamine against dopaminergic nigrostriatal neurons is blocked by the N-methyl-D-aspartate (NMDA) receptor antagonist MK-801. As these neurons degenerate selectively in Parkinsonism it may be postulated that an endogenous excitotoxin is instrumental in causing the disease. Thus it may be speculated that nigrostriatal neurons are sensitive to a sequence of events in which either physical trauma or some toxic agent induces oxidative stress resulting in the release of excitatory amino acids that damage the nigrostriatal dopaminergic cells.

DRUG TREATMENT OF PARKINSON'S DISEASE Aetiology of Parkinson's disease

Symptoms of Parkinson's disease only arise when more than 50% of the nigrostriatal dopaminergic cells are lost. By contrast, drug-induced parkinsonism, arising from the chronic administration of classical neuroleptics such as haloperidol, occurs when about 80% of the dopaminergic receptors (D2) are blocked. Normal ageing is also associated with loss of cells from the basal ganglia but the rate of cell loss is only about 10% of that found in patients with Parkinson's disease. Thus Parkinson's disease, like any of the dementias, is not an inevitable product of ageing.

The familial form of the disease, in which the age of onset may be as early as 20 years, is rare but studies of the genetic basis have enabled genetic markers to be described. Thus the gene for the protein parkin has been iocated on chromosome 6 and alpha-synuclein on chromosome 4. Locomotor deficits have been found in mice in which alpha-synuclein is dysfunctional but the precise physiological role of this protein is unclear. With regard to parkin, which appears to be abnormal in most patients with juvenile onset Parkinson's disease, it has been shown that this protein is located in the substantia nigra and locus coeruleus where it plays a role in protein degradation. This suggests that a mutation of parkin leads to an abnormal accumulation of proteins in the substantia nigra leading to early apoptosis of these cells.

With regard to the late onset, and common, form of the disease, one of the most popular theories suggests that free radicals accumulate and cause cellular injury leading to neuronal degeneration. This is known as the oxidative stress hypothesis and postulates that as the major pathway leading to the oxidative deamination of dopamine is via MAO-B, hydrogen peroxide is an essential end-product. Hydrogen peroxide then reacts with ferrous or cuprous ions which are present in the substantia nigra to form highly reactive hydroxyl radicals. Dopamine can also react non-enzymati-cally with oxygen to form quinines and semiquinones together with O2*, OH* and hydrogen peroxide. The substantia nigra is a rich source of neuromelanin (the black pigment which gives it the name) which is formed from the auto-oxidation of dopamine. This process also generates the toxic quinines and reactive oxygen species. These three processes may therefore contribute to the destruction of the dopamine-rich cells in the striatum and therefore be responsible for the common form of Parkinson's disease that occurs in the elderly.

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