Methylphenyltetrahydropyridine

The first case of methyl-phenyl-tetrahydropyridine (MPTP)-induced parkinsonism was reported in 1979. y The subject later died of a drug overdose. At autopsy, destruction of the substantia nigra zona compacta was evident; other areas usually involved in Parkinson's disease such as the locus coeruleus were not affected. This article lay dormant until parkinsonism began appearing in the San Francisco Bay area among users of MPTP sold as "synthetic heroin." The responsible chemical was identified as a byproduct of meperidine synthesis, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). y

The cerebrospinal fluid (CSF) of affected patients contains decreased homovanillic acid levels similar to those observed in patients with Parkinson's disease. y Positron-emission tomography (PET) using 18F-dopa of asymptomatic drug users exposed to MPTP showed decreased dopa uptake, which suggests that the numbers of DA terminals and, by extension, the nigral cell bodies were decreased. The MPTP model of dopamine depletion has been helpful in mechanistic studies of the degenerative and regenerative potential of the nigrostriatal DA system. MPTP is metabolized to 1-methyl-4-phenylpyridinium (MPP+) by monoamine oxidase B. MPP+ is then taken up into DA terminals, where it blocks complex I of the mitochondrial respiratory chain. This blockage may lead to adenosine triphosphate (ATP) depletion with secondary cellular demise due to energy crisis. The possibility that abnormalities in the respiratory chain could also lead to cytotoxic oxygen-based free radicals has also been put forward. y

MPTP has also caused parkinsonism in laboratory workers who were accidentally contaminated through inhalation or skin contact. Bradykinesia and rigidity can be very severe, with muteness and inability to swallow. As in idiopathic Parkinson's disease, levodopa/carbidopa and bromocriptine can provide dramatic relief in these patients. Patients develop typical side effects of these drugs, including dyskinesia, on-off phenomenon, and psychiatric symptoms.

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