4-Phenylpyridine (4PP) and MPTP: the relationship between striatal MPP+ concentrations and neurotoxicity

Because of the chemical and structural similarity between 4-phenylpyridine (4PP) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), the effects of 4PP alone and in combination with MPTP on striatal dopamine (DA) concentrations were studied in mice. 4PP did not deplete striatal DA, even when given in maximally tolerated doses (five times that required for MPTP neurotoxicity). However, when 4PP was administered prior to MPTP, it provided significant protection against the DA-depleting effects of MPTP. Additional experiments showed that 4PP pretreatment reduced striatal concentrations of 1-methyl-4-phenylpyridinium ion (MPP+) - the putative toxic biotransformation product of MPTP, and that the concentration of this metabolite closely mirrored striatal DA depletion in MPTP-treated mice. In vitro studies established that 4PP probably lowers MPP+ concentrations by inhibiting the biotransformation of MPTP to MPP+. These observations could be of clinical interest in view of the lower incidence of cigarette smoking among Parkinson's disease patients, and the fact that 4PP is known to be present in cigarettes.