MPP(+)-like neurotoxicity of a pyridinium metabolite derived from haloperidol: in vivo microdialysis and in vitro mitochondrial studies.
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.
Rollema
H
H
Department of Medicinal Chemistry, University Center for Pharmacy, Groningen, The Netherlands.
Skolnik
M
M
D'Engelbronner
J
J
Igarashi
K
K
Usuki
E
E
Castagnoli
N
N
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
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