1-Methyl-4-phenylpyridinium-like neurotoxicity of a pyridinium metabolite derived from haloperidol: cell culture and neurotransmitter uptake studies

J Bloomquist, E King, A Wright, C Mytilineou, K Kimura, K Castagnoli and N Castagnoli

Department of Entomology, Virginia Polytechnic Institute and State University, Blacksburg.

It is now generally accepted that the nigrostriatal degenerative properties of the parkinsonian-inducing agent 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine are mediated by the brain monoamine oxidase B generated 1-methyl-4-phenylpyridinium metabolite (MPP+). In this article, the results are described of ongoing efforts to evaluate the MPP(+)-type neurotoxic potential of the haloperidol (HP)-derived pyridinium metabolite HPP+, a 1,4-disubstituted structural analog of MPP+, which is formed in humans and rats treated with HP. Previous studies in the rat have shown that intrastriatal perfusion of HPP+ leads to the irreversible depletion of striatal dopamine and serotonin. Furthermore, HPP+ was a potent inhibitor of NADH-supported mitochondrial respiration. This article reports that HPP+ also is toxic to dopaminergic and serotonergic neurons in cultures of embryonic mesencephalic cells, as measured by loss of the ability of exposed cells to accumulate tritium-labeled dopamine and serotonin and by immunochemical staining techniques. HPP+ also inhibited the uptake of these labeled neurotransmitters by synaptosomes prepared from mouse neostriata (dopamine) and cortical tissues (serotonin). Because HP is unlikely to be a substrate for brain monoamine oxidase B, the production and accumulation of HPP+ in the brain is probably not comparable to that of MPP+. On the other hand, chronic exposure to HP could result in brain levels of this lipophilic quaternary pyridinium species that might coincide with the late-appearing tardive dyskinesias that are observed in some HP-treated patients months and, more often, years after the initiation of HP therapy.

Volume 270, Issue 2, pp. 822-830, 08/01/1994
Copyright © 1994 by American Society for Pharmacology and Experimental Therapeutics

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