BIOCHEMICAL ASPECTS OF PARKINSONS-DISEASE

The importance of the striatal dopamine (DA) deficiency and the DA sub stituting property of levodopa for the pathophysiology and therapy of Parkinson's disease (PD) is reiterated. In addition, it is shown that in PD, significantly reduced DA levels are also found in the nucleus a ccumbens, external and internal segments of the globus pallidus, the s ubstantia nigra reticulata, and the subthalamic nucleus. It is propose d that, in addition to the critical role played by the striatal DA los s, the DA changes in the extrastriatal nuclei of the basal ganglia are importantly involved in the pathophysiologic mechanisms resulting in the parkinsonian movement disorder, and that the therapeutic and/or si de effects of DA substitution therapy may, in part, be mediated throug h these brain regions which, like the striatum, suffer Daergic deaffer entation in PD. From observations in brain of patients with secondary parkinsonism, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine parkinsonis m in the rhesus monkey, as well as the regional DA transporter distrib ution in the primate substantia nigra, it is concluded that PD may be caused by any exogenous and/or endogenous toxin using the transporter system for DA and to some degree the other brain monoamines (noradrena line, serotonin), to enter, and damage, the respective monoamine neuro ns. Based on converging evidence, the view is advanced that endogenous , genetically based (excessive) formation, or accumulation, of toxic D A transporter substrates, such as isoquinoline or P-carboline derivati ves, may in fact represent the primary cause of substantia nigra cell degeneration in patients with PD.