The significance of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine

Abstract

The chance occurrence of an outbreak of persistent parkinsonism amongst young drug addicts abusing a synthetic pethidine derivative has aroused considerable interest. The offending agent, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), has to be converted by monoamine oxidase B perhaps in glia, into the neurotoxin, 1-methyl-4-phenylpyridinium (MPP+). MPP+ is then taken up into dopaminergic neurons by the normal dopamine re-uptake system. Once within dopaminergic neurons it binds to neuromelanin, so is retained to kill nerve cells, perhaps by generation of free radicals and other toxic species. MPTP produces parkinsonism in primates (but not in many lower species, probably because they possess little or no neuromelanin). MPTP toxicity in primates can be prevented by treatment with monoamine oxidase inhibitors, or by inhibitors of dopamine re-uptake, and to some extent by antioxidants. Toxicity of MPTP is remarkably selective. It preferentially destroys the substantia nigra pars compacta, but may spare the adjacent pigmented ventral tegmental areas, as well as other neuronal systems. However, selectivity decreases with age: MPTP causes more widespread damage in older animals. Affected individuals exhibit all symptoms and signs of Parkinson's disease. As well as providing an accurate animal model of the illness, MPTP is one of the first environmental neurotoxins known to cause parkinsonism in humans. This observation has led to reappraisal of the epidemiology of the illness and a search for similar environmental agents. Understanding the mechanism of MPTP toxicity has also provided suggestions on how to treat the cause of Parkinson's disease.