FLUNARIZINE AND CINNARIZINE INHIBIT MITOCHONDRIAL COMPLEX-I AND COMPLEX-2 - POSSIBLE IMPLICATION FOR PARKINSONISM

被引:0
作者
VEITCH, K
HUE, L
机构
[1] UNIV LOUVAIN, SCH MED, HORMONE & METAB RES UNIT, B-1200 BRUSSELS, BELGIUM
[2] INT INST CELLULAR & MOLEC PATHOL, B-1200 BRUSSELS, BELGIUM
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中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Cinnarizine and flunarizine are piperazine derivatives with calcium antagonist and anticonvulsant properties and are used widely in the treatment of vertigo and circulatory disorders. They have been implicated recently in the aggravation, or even the induction, of parkinsonism in elderly patients. Because the aetiology of parkinsonism has been suggested as having a mitochondrial component, we have investigated the effects of both compounds on mitochondrial respiration and on the activities of the individual respiratory chain complexes. In intact mitochondria from rat liver, both drugs inhibited respiration rates, with substrates entering at Complex I (glutamate/malate) and Complex II (succinate). These effects could be explained by potent inhibitions (K-i 3-10 mu M) Of both complexes. Complex I is inhibited at a site near the ubiquinone-binding site, which is not competitive with respect to ubiquinone, whereas the inhibition of Complex II is apparently caused by competition with ubiquinone. Furthermore, the inhibition of NADH oxidation by flunarizine in submitochondrial particles caused an NADH-dependent generation of superoxide. These inhibitory properties of both compounds could be significant factors in the aggravation or induction of parkinsonism in elderly patients, in whom mitochondrial function already may be impaired.
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页码:158 / 163
页数:6
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