title: MPP(+)-like neurotoxicity of a pyridinium metabolite derived from haloperidol: in vivo microdialysis and in vitro mitochondrial studies.
abstract: Intracerebral (intrastriatal, intranigral and intracortical) microdialysis studies were conducted in conscious rats to investigate the comparative dopaminergic and serotonergic neurotoxic potential of the pyridinium metabolite 4-(4-chlorophenyl)-1-[4-(4-fluorophenyl)-4-oxobutyl]pyridinium (HPP+), derived from the extensively used neuroleptic agent haloperidol and 1-methyl-4-phenylpyridinium (MPP+), the pyridinium metabolite derived from the parkinsonian inducing agent 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Although HPP+ was less potent than MPP+ on the dopaminergic system, the two compounds displayed comparable toxic effects on the serotonergic system. HPP+ also proved to be a weaker inhibitor of mitochondrial respiration than MPP+ in vivo as measured by increases in extracellular lactate levels. On the other hand, HPP+ was a more potent inhibitor of mitochondrial respiration in vitro than MPP+, with IC50 values of 12 microM (HPP+) and 160 microM (MPP+). Quantitative estimations established that the concentrations of the more hydrophobic HPP+ in the brain tissues surrounding the microdialysis probe were less than those of MPP+ after comparable perfusions. Consequently, the inherent toxicity of HPP+ relative to MPP+ may be greater than suggested by the results observed in the microdialysis experiments. These data support previous speculations that HPP+ may contribute to some of the persistent extrapyramidal side effects associated with chronic haloperidol treatment.
authors.affiliation: Department of Medicinal Chemistry, University Center for Pharmacy, Groningen, The Netherlands.
authors.forename: H
authors.initials: H
authors.lastname: Rollema
authors.forename: M
authors.initials: M
authors.lastname: Skolnik
authors.forename: J
authors.initials: J
authors.lastname: D'Engelbronner
authors.forename: K
authors.initials: K
authors.lastname: Igarashi
authors.forename: E
authors.initials: E
authors.lastname: Usuki
authors.forename: N
authors.initials: N
authors.lastname: Castagnoli
mesh_terms: D015655:1-Methyl-4-phenylpyridinium / Q000633:toxicity*; D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000187:drug effects; D004298:Dopamine / Q000378:metabolism; D006220:Haloperidol / Q000031:analogs & derivatives* / Q000633:toxicity; D007773:Lactates / Q000096:biosynthesis; D019344:Lactic Acid; D008297:Male; D051379:Mice; D017551:Microdialysis; D008930:Mitochondria, Liver / Q000187:drug effects; D009420:Nervous System / Q000187:drug effects*; D011726:Pyridinium Compounds / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D011954:Receptors, Dopamine / Q000187:drug effects; D011985:Receptors, Serotonin / Q000187:drug effects; D012701:Serotonin / Q000378:metabolism
chemical_list: D007773:Lactates; D011726:Pyridinium Compounds; D011954:Receptors, Dopamine; D011985:Receptors, Serotonin; D015102:3,4-Dihydroxyphenylacetic Acid; C085216:N-(4'-fluorobutyrophenone)-4-(4-chlorophenyl)pyridinium; D012701:Serotonin; D019344:Lactic Acid; D006220:Haloperidol; D015655:1-Methyl-4-phenylpyridinium; D004298:Dopamine