MPP(+)-like neurotoxicity of a pyridinium metabolite derived from haloperidol: In vivo microdialysis and in vitro mitochondrial studies
| Autor: | Rollema, H, Skolnik, M, D'Engelbronner, J, Castagnoli Jr, N, Igarashi, K, Usuki, E, ROLLEMA, H, WESTERINK, BHC, DRIJFHOUT, WJ |
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| Jazyk: | angličtina |
| Rok vydání: | 1991 |
| Zdroj: | MONITORING MOLECULES IN NEUROSCIENCE, 367-369 STARTPAGE=367;ENDPAGE=369;TITLE=MONITORING MOLECULES IN NEUROSCIENCE |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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