Etiology

The signs and symptoms of parkinsonism are caused by a decrease in striatal dopamine due to the loss of dopaminergic neurons in the substantia nigra of the midbrain. At the present time, environmental agents are the primary known cause of parkinsonism; exposure to manganese, carbon disulfide, and carbon monoxide are recognized environmental toxins that can produce the disorder. It is also known that drugs that interfere with dopaminergic pathways or receptors - such as phenothiazines, reserpine, and alpha-methyldopa - can produce the Parkinson's syndrome, and multiple head traumas, probably causing atrophy of the substantia nigra, also may do the same. The recent discovery that 1-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP), a commercially available chemical intermediate used in the synthesis of organic compounds, induces parkinsonism, has again supported the concept that environmental chemicals play a major role in the pathogenesis of this disorder. Varying amounts of MPTP may be formed as a byproduct in the synthesis of potent analgesic drugs, one of which is MPPP (l-methyl-4-phenyl-4-proprionoxypiperi-dine), the reverse ester of meperidine, a strong analgesic drug similar to heroin and morphine. The self-administration of small amounts of MPTP by young drug abusers who were using MPPP as an alternative to heroin has resulted in a severe and permanent Parkinson's syndrome that resembles Parkinson's disease in its clinical, pathological, and biochemical features as well as its responsiveness to the drugs usually used in the treatment of Parkinson's patients. Primate models of parkinsonism using MPTP demonstrate that a Parkinson-like syndrome can be produced in the monkey, and it is now known that metabolic conversion by monoamine oxidase B of MPTP to MPP+ (l-methyl-4-phenyl-pyridinium) is the reaction that results in the ultimate toxin MPP+. It therefore follows that blocking monoamine oxidase B with a selective inhibitor such as L-deprenyl completely prevents the toxicity of MPTP, but administration of a selective monoamine oxidase A inhibitor such as clorgylin does not. Thus, MPTP turns out to be the first toxin positively known to cause Parkinson's disease whose neuropharmacology is known and whose toxicity can be prevented by preventing its metabolic conversion to the ultimate toxin, which is MPP+ (see Figure VIII.102.1).

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