The cause of the degeneration of
dopamine-containing cells in the
zona compacta of the substantia nigra in
Parkinson's disease remains unknown. The ability of the selective nigral toxin 1-methyl-4-phenyl-1,2,3,6
tetrahydropyridine (
MPTP) (via its metabolite MPP+) to destroy nigral
dopamine cells selectively by inhibiting complex I of the mitochondrial energy chain may provide a clue. Indeed, recent studies of post-mortem brain tissue have suggested the presence of an on-going toxic process in the substantia nigra in
Parkinson's disease leading to excess lipid peroxidation. This appears also to involve a disruption of mitochondrial function since mitochondrial
superoxide dismutase activity is increased and there is impairment of complex I. These changes may in turn relate to a selective increase in the total
iron content of substantia nigra coupled to a generalised decrease in brain
ferritin content.
Piribedil is used in the symptomatic treatment of
Parkinson's disease and is particularly effective against
tremor.
Piribedil (and its metabolites) acts as a
dopamine D-2 receptor agonist. However, in our studies in contrast to other
dopamine agonists, in vivo
piribedil interacts with
dopamine receptors in the substantia nigra and nucleus accumbens but not those in the striatum. In patients with
Parkinson's disease the beneficial effects of
piribedil may be limited by
nausea and drowsiness. Indeed, in
MPTP-treated primates
piribedil reverses motor deficits but marked side-effects occur. However, pre-treatment with the peripheral
dopamine receptor antagonist domperidone prevents the unwanted effects and
piribedil produces a profound and longer-lasting reversal of all components of the motor syndrome.(ABSTRACT TRUNCATED AT 250 WORDS)