Biomaterial Database

Flunarizine and cinnarizine inhibit mitochondrial complexes I and II: possible implication for parkinsonism. 1994

K Veitch, and L Hue

Hormone and Metabolic Research Unit, University of Louvain Medical School, Brussels, Belgium.

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 (Ki 3-10 microM) 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.

UI	MeSH Term	Description	Entries
D008929	Mitochondria, Heart	The mitochondria of the myocardium.	Heart Mitochondria,Myocardial Mitochondria,Mitochondrion, Heart,Heart Mitochondrion,Mitochondria, Myocardial
D008930	Mitochondria, Liver	Mitochondria in hepatocytes. As in all mitochondria, there are an outer membrane and an inner membrane, together creating two separate mitochondrial compartments: the internal matrix space and a much narrower intermembrane space. In the liver mitochondrion, an estimated 67% of the total mitochondrial proteins is located in the matrix. (From Alberts et al., Molecular Biology of the Cell, 2d ed, p343-4)	Liver Mitochondria,Liver Mitochondrion,Mitochondrion, Liver
D009097	Multienzyme Complexes	Systems of enzymes which function sequentially by catalyzing consecutive reactions linked by common metabolic intermediates. They may involve simply a transfer of water molecules or hydrogen atoms and may be associated with large supramolecular structures such as MITOCHONDRIA or RIBOSOMES.	Complexes, Multienzyme
D010088	Oxidoreductases	The class of all enzymes catalyzing oxidoreduction reactions. The substrate that is oxidized is regarded as a hydrogen donor. The systematic name is based on donor:acceptor oxidoreductase. The recommended name will be dehydrogenase, wherever this is possible; as an alternative, reductase can be used. Oxidase is only used in cases where O2 is the acceptor. (Enzyme Nomenclature, 1992, p9)	Dehydrogenases,Oxidases,Oxidoreductase,Reductases,Dehydrogenase,Oxidase,Reductase
D010302	Parkinson Disease, Secondary	Conditions which feature clinical manifestations resembling primary Parkinson disease that are caused by a known or suspected condition. Examples include parkinsonism caused by vascular injury, drugs, trauma, toxin exposure, neoplasms, infections and degenerative or hereditary conditions. Clinical features may include bradykinesia, rigidity, parkinsonian gait, and masked facies. In general, tremor is less prominent in secondary parkinsonism than in the primary form. (From Joynt, Clinical Neurology, 1998, Ch38, pp39-42)	Atherosclerotic Parkinsonism,Secondary Parkinsonism,Symptomatic Parkinson Disease,Parkinson Disease, Secondary Vascular,Parkinson Disease, Symptomatic,Parkinsonism, Secondary,Parkinsonism, Symptomatic,Secondary Vascular Parkinson Disease,Parkinsonism, Atherosclerotic,Secondary Parkinson Disease,Symptomatic Parkinsonism
D002936	Cinnarizine	A piperazine derivative having histamine H1-receptor and calcium-channel blocking activity with vasodilating and antiemetic properties but it induces PARKINSONIAN DISORDERS.	1-(Diphenylmethyl)-4-(3-phenyl-2-propenyl)piperazine,Cinarizina Inkey,Cinarizina Ratiopharm,Cinarizine,Cinazière,Cinna,Cinnarizin AL,Cinnarizin Siegfried,Cinnarizin Von Ct,Cinnarizin-Ratiopharm,Cinnarizine L-Tartrate,Cinnarizine L-Tartrate (1:1),Cinnarizine, (E)-Isomer,Cinnarizine, Dihydrochloride,Cinnipirine,Cisaken,Dimitronal,R-516,Stugeron,Stugeron Forte,Cinnarizin Ratiopharm,Cinnarizine L Tartrate,Dihydrochloride Cinnarizine,L-Tartrate, Cinnarizine,R 516,R516,Von Ct, Cinnarizin
D004579	Electron Transport	The process by which ELECTRONS are transported from a reduced substrate to molecular OXYGEN. (From Bennington, Saunders Dictionary and Encyclopedia of Laboratory Medicine and Technology, 1984, p270)	Respiratory Chain,Chain, Respiratory,Chains, Respiratory,Respiratory Chains,Transport, Electron
D005444	Flunarizine	Flunarizine is a selective calcium entry blocker with calmodulin binding properties and histamine H1 blocking activity. It is effective in the prophylaxis of migraine, occlusive peripheral vascular disease, vertigo of central and peripheral origin, and as an adjuvant in the therapy of epilepsy.	Flunarizin,Flunarizine Dihydrochloride,Flunarizine Hydrochloride,R-14950,Sibelium,Dihydrochloride, Flunarizine,Hydrochloride, Flunarizine,R 14950,R14950
D000818	Animals	Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA.	Animal,Metazoa,Animalia
D013367	Submitochondrial Particles	The various filaments, granules, tubules or other inclusions within mitochondria.	Particle, Submitochondrial,Particles, Submitochondrial,Submitochondrial Particle