| Autor: |
ROLLEMA, H, SKOLNIK, M, DENGELBRONNER, J, IGARASHI, K, USUKI, E, CASTAGNOLI, N |
| Přispěvatelé: |
Groningen Research Institute of Pharmacy |
| Jazyk: |
angličtina |
| Rok vydání: |
1994 |
| Předmět: |
|
| Zdroj: |
Journal of Pharmacology and Experimental Therapeutics, 268(1), 380-387. WILLIAMS & WILKINS |
| ISSN: |
0022-3565 |
| 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 mu M (HPP+) and 160 mu M (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 |
| Externí odkaz: |
|
