TETRAHYDROISOQUINOLINES AND PARKINSON'S DISEASE

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DESCRIPTION (provided by applicant): Twin and epidemiological studies suggest that environmental factors contribute to the development of idiopathic Parkinson's disease. Possible non-genetic risk factors for Parkinson's disease include well water use, rural living, and exposure to pesticides and herbicides. The insecticide rotenone can inhibit complex I of the respiratory chain and cause Parkinsonism in rats. The more striking association of the "synthetic heroin" adulterant MPTP with the development of Parkinsonism in young adults stimulated interest in other possible exogenous toxins that may cause cell death in the substantia nigra. Tetrahydroisoquinoline derivatives are endogenous and exogenous neurotoxins that have been shown to produce dopaminergic dysfunction and cell death in various model systems. Some tetrahydroisoquinoline derivatives have been detected in foods and some of these compounds can cross the blood-brain barrier. Tetrahydroisoquinoline derivatives can also be formed endogenously by condensation of catecholamines with aldehydes. Critical unanswered questions remain regarding the role of tetrahydroisoquinoline derivatives in neurodegeneration. This project will test three interrelated hypotheses: (1) tetrahydroisoquinoline derivatives accumulate in central nervous system neurons, particularly dopaminergic, with normal aging, (2) tetrahydroisoquinoline derivatives can cause apoptotic cell death of dopaminergic neurons in rodents, and (3) tetrahydroisoquinoline and one or more of its derivatives are present in a variety of fruits and vegetables. Tetrahydroisoquinoline derivatives may accumulate in neurons through various combinations of endogenous and/or exogenous pathways. Normal metabolic pathways may "inadvertently" convert compounds such as dopamine to toxic by-products such as 1,2-dimethyl-6,7-dihydroxyisoquinolium ion. Neuronal or glial enzymes may also convert exogenous chemicals present in foods such as tetrahydroisoquinoline to the neurotoxin, N-methylisoquinolinium ion. Evolution may have not provided neurons with mechanisms to prevent accumulation of these by-products of normal metabolism and, as a consequence, susceptible neuronal populations may slowly undergo apoptotic death in the elderly.