PARKINSONS-DISEASE - PAST, PRESENT, AND FUTURE

The development of understanding of the pathophysiology and modes of treatment of Parkinson's disease represents one of the triumphs of modern medicine, encompassing astute clinical observation, utilization of basic research findings regarding dopamine to develop the first rational treatment of a degenerative disorder of the central nervous system, and remains at the frontiers of neurologic science. After characterization of the clinical and pathologic features of Parkinson's disease, rational treatment awaited the discovery of the deficit in basal ganglia dopamine. On the basis of this observation and the known biosynthetic pathways for dopamine formation, levodopa was introduced. Use of metabolic inhibitors to prolong and potentiate the effects and avoid the deleterious side effects of levodopa enhanced the efficacy of this neurotransmitter replacement strategy. The discovery and characterization of dopamine receptor subtypes and the availability of selective dopamine agonists provided additional therapeutic approaches, but failed to address the underlying cause of the degenerative process. The discovery and disclosure of the mechanisms of toxicity of the relatively selective nigrostriatal neurotoxin, 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP), triggered a resurgence of interest in etiological factors which might contribute to the development of parkinsonism and together with the report that inhibition of monoamine oxidase B with deprenyl not only potentiated the effects of levodopa, but appeared to prolong the life of parkinsonian patients, resulted in a large-scale trial of drugs that might arrest the degenerative process. Furthermore, the MPTP primate model of Parkinson's disease has encouraged development of fetal mesencephalic and other tissue implant approaches to reversal of parkinsonism. Although much of this is still in the experimental stages, hopes are high that new and more effective therapies will be developed and that similar techniques might be applicable to a wide variety of neuropsychiatric disorders.