PathophysioIogy of Parkinson's disease

The cause of idiopathic Parkinson's disease has not been established, however a number of chemically diverse compounds are implicated as aetiolologicaI agents The selective nigral neurotoxin, 1 -methyl-4-phen yI-1 ,2,3,6-tetrahydropyridine (MPTP) induces a persistent Parkinsonism in man and other primates and has been used extensively to induce an experimental parkinsonism in order to study the mechanisms of cell death in PD. Use of the chemically-related pesticide paraguat, has been shown to have a positive correlation with the incidence of Parkinson's disease in an epidemiological study. Long term occupational exposure to manganese affects the nervous system, producing chronic extrapyramidal symptoms similar to those seen in Parkinson's disease, with specific damage to the neuromelanin containing cells of the substantia nigra Iron has also been suggested to play a role in cell death in Parkinso n's disease. Factors common to these compounds are their ability to participate in free radical reactions and their affinity for neuromelanin

Evidence for the involvement of free-radical reactions in the pathophysiology of PD comes from studies on idiopathic Parkinson's disease. Glutathione and glutathione peroxidase in the substantia nigra of Parkinsonian patients is decreased. Both glutathione and glutathione peroxidase are involved in the reduction of hydrogen peroxide and organic peroxides. E.g. lipid Increased intra-nigral iron concentrations decreased levels of brain femtin, increased lip peroxidation, and increased superoxide dismutase levels, have also been found in the substantia nigra of Parkinsonian pa patients This combination of reduced antioxidant levels renders the substantia nigra susceptible to any further insult.

There is a direct relationship between the distribution of neuromelanin-containing cells in the substantia nigra and the pattern of cell loss in idiopathic Parkinson's disease. It has been suggested that the synthesis and accumulation of neuromelanin, with the associated injury resulting from autoxidative products of catecholamine oxidation, confers a susceptibility to degeneration to these cells. Neuromelanin, in contrast to eumelanin, is not seguestered within membrane bound organelles and has a high affinity for potentially toxic nucleophiles, including those toxins implicated in the aetiology of Parkinson's disease. Therefore the susceptibility of pigmented dopaminergic neurones to degeneration is likely to be exacerbated by exogenous or endogenous free radical generating cornpounds.

The preferential loss of melaninised cells in Parkinson's disease suggests that this pigment plays role in the susceptibility and vulnerability of these cells. In vivo neuromelanin is frequently bound to lipofuscin granules and is localised to catecholaminergic neurones of the substantia nigra, locus coerulus and other brain stem nuclei in primate brains Th vivo deposition of mature neuromelanin is seen from the age of 6 months, increasing with aging up to 60 years after wich there is a decrease, a decrease which is accelerated in Parkinson's disease with preferential loss of the heavily pigmented cells. Although deposition of neuromelanin is not seen microscopically until after the age ot 6 months, it is probable that dopamine oxidation, itself a free radical generating reaction, is an ongoing process. Apparent disappearance may be related to loss of extended conjugated structure of neuromelanin which lead to loss of the characteristic pathochromicity (absorbance in visible spectrum). The conditions necessary for the formation of neuromelanin are not known.

Dopanmine oxidation.

1: enzymatic oxidation

DA +O₂ àMAO à3,4-dihydroxyphenylpacetaldehyde + NH3 + H2O2

2: auto-oxidation

DA + O2 à (semiquinone + O ) + (H+)

DA + O2 + 2H+ ---> semiquinone + H₂O₂

A decrease in complex 1 of the mitochondrial respiratory chain has also been found in patients with Parkinson's disease and with MPTP-induced parkinsonism. Complex 1 is comprised of 26 peptides, 7 of which are encoded by the mitochondrial DNA, which is itself particularly vulnerable to free radical damage since it lacks the associated histone proteins of nuclear DNA. A reduction in the cellular energy potential as an result of inadequate respiration is likely to lead to a rise in cytosolic calcium as the ATP-dependent capacity of the cell to extrude calcium is compromised. Subsequent activation of calcium-dependent proteases, lipases and endonuclease enzymes could lead to cellular damage and secondary production of free radicals. Inhibition of ATP synthesis as a result of an mitochondrial defect would also compromise glutathione production and therefore reduce the antioxidant capacity of the cell. It has also been proposed that mitochondrial defect may lead to a secondary excitotoxic damage by reducing the voltage-dependent magnesium blockade on BAA receptors.

It seems clear that free radicals many be involved as a primary mechanism of cell damage in this neurodegenerative diseas, the selectivity for the dopaminergic neurones of the substantian nigra may be related to their high affinity dopamine uptake receptors, their high endogenous level of dopamin and the presence of neuromelanin.