Gillis JC, Benefield P, McTavish D.

Adis International Limited,
Auckland, New Zealand.
Drugs Aging 1994 Aug;5(2):133-52

ABSTRACT

Idebenone is a benzoquinone compound which has been investigated in elderly patients with dementia. Its precise mechanism(s) of action remains unknown, but in vitro and in vivo studies suggest the drug may diminish nerve cell damage due to ischaemia, correct neurotransmitter defects and/or cerebral metabolism and facilitate memory and learning. In the small number of studies available for evaluation, idebenone was generally superior to placebo and comparable with bifemelane, oxiracetam and nebracetam on the basis of a number of objective and subjective tests and rating scales in patients with mild to moderate cognitive decline. Clinical trial results indicate that patients with mild dementia seem more likely to respond than those with greater functional decline. The degree of benefit conferred by idebenone is often difficult to determine, but in those who respond, improvement is generally mild to moderate. Therapy with idebenone appears well tolerated for up to 2 years, and no changes in vital signs or laboratory values have been seen in clinical trials. In view of the lack of a proven agent to limit or halt the progression of dementia in the elderly, idebenone may warrant consideration in patients with mild cognitive dysfunction on the basis of preliminary evidence of predominantly mild improvement of functional status in some patients and good tolerability. However, further well designed studies, including comparisons with newer and commonly used agents, such as tacrine, are required to better define the role of idebenone in this complex area of treatment.

Hirai K, Hayako H, Kato K, Miyamoto M.

Pharmaceutical Research Division,
Takeda Chemical Industries Ltd., Osaka, Japan
Naunyn Schmiedebergs Arch Pharmacol 1998 Nov;358(5):582-5

ABSTRACT

The application of amyloid beta-peptide (Abeta) 1-40 (10 microM) caused neurodegeneration of hippocampal neuronal cells, as indicated by the release of lactate dehydrogenase (LDH) into the culture medium. Treatment with idebenone (10-1000 nM), a potent antioxidant in mitochondria, protected the hippocampal neurons against the Abeta1-40(10 microM)-induced neurotoxicity. To determine the morphological change in neurons during the Abeta1-40-induced cytotoxicity, the cells were immunostained with anti-MAP2 antibodies. After 4-day exposure to 10 microM Abeta1-40, the number of neurons was reduced, and the surviving neurons had an apparently reduced number of neurites which were shorter than those of control neurons. When idebenone was added to the culture medium with Abeta1-40, the number of surviving neurons was significantly increased, and their neurites were as long as seen in control culture. These results suggest that reactive oxygen species mediate neurotoxicity of Abeta1-40, and idebenone protects neurons against the Abeta1-40-induced neurotoxicity.

Shivaram KN, Winklhofer-Roob BM, Straka MS,
Devereaux MW, Everson G, Mierau GW, Sokol RJ.

Department of Pediatrics,
University of Colorado School of Medicine,
Denver, CO USA

ABSTRACT

Oxidant stress induced by hydrophobic bile acids has been implicated in the pathogenesis of liver injury in cholestatic liver disorders. We evaluated the effect of idebenone, a coenzyme Q analogue, on taurochenodeoxycholic acid (TCDC)-induced cell injury and oxidant stress in isolated rat hepatocytes and on glycochenodeoxycholic acid (GCDC)-induced generation of hydroperoxides in fresh hepatic mitochondria. Isolated rat hepatocytes in suspension under 9% oxygen atmosphere were preincubated with 0, 50, and 100 micromol/l idebenone for 30 min and then exposed to 1000 micromol/l TCDC for 4 h. LDH release (cell injury) and thiobarbituric acid reactive substances (measure of lipid peroxidation) increased after TCDC exposure but were markedly suppressed by idebenone pretreatment. In a second set of experiments, the addition of 100 micromol/l idebenone up to 3 h after hepatocytes were exposed to 1000 micromol/l TCDC resulted in abrogation of subsequent cell injury and markedly reduced oxidant damage to hepatocytes. Chenodeoxycholic acid concentrations increased to 5.15 nmol/10(6) cells after 2 h and to 7.05 after 4 h of incubation of hepatocytes with 1000 micromol/l TCDC, and did not differ in the presence of idebenone. In freshly isolated rat hepatic mitochondria, when respiration was stimulated by succinate, 10 micromol/l idebenone abrogated the generation of hydroperoxides during a 90-minute exposure to 400 micromol/l GCDC. These data demonstrate that idebenone functions as a potent protective hepatocyte antioxidant during hydrophobic bile acid toxicity, perhaps by reducing generation of oxygen free radicals in mitochondria.

Mordente A, Martorana GE, Minotti G, Giardina B.

Institute of Biological Chemistry,
Catholic University School of Medicine, Rome, Italy.

Chem Res Toxicol 1998 Jan;11(1):54-63

Abstract

Idebenone is a synthetic analogue of coenzyme Q that is currently employed in the treatment of vascular and degenerative diseases of the central nervous system. There is some evidence to suggest that idebenone might function as an antioxidant; however, it has not been demonstrated whether this function pertains to the quinone or hydroquinone form of idebenone. Here we demonstrate that idebenone can scavenge a variety of free radical species, including organic radicals such as 2,2′-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) and diphenylpicrylhydrazyl, peroxyl and tyrosyl radicals, and peroxynitrite. Idebenone can also redox couple with hypervalent species of Mb or Hb, thus preventing lipid peroxidation promoted by these species. Likewise, idebenone inhibits microsomal lipid peroxidation induced by ADP-iron complexes or organic hydroperoxides. In so doing, idebenone prevents the destruction of cytochrome P450, which otherwise would accompany lipid peroxidation. Irrespective of the experimental system under investigation, idebenone functions by virtue of the electron-donating properties of the hydroquinone form. Redox coupling of this hydroquinone with free radicals generates the quinone compound, which per se lacks antioxidant activity. In many experiments, the antioxidant effects of idebenone become appreciable at approximately 2 microM, which is well in the range of plasma levels attainable in patients given oral doses of this drug. Moreover, comparative experiments have shown that the antioxidant efficiency of idebenone varies from no less than 50% to slightly more than 100% of that of vitamin E or Trolox. We would therefore propose that the neuroprotective effects of idebenone can be attributed, at least in part, to its ability to function as an antioxidant, involving redox cycling between hydroquinone and quinone.

Suno M, Nagaoka A.

Central Research Division,
Takeda Chemical Industries, Ltd., Osaka, Japan
Arch Gerontol Geriatr 1989 May;8(3):299-305

ABSTRACT

The effects of idebenone on the swelling of rat brain mitochondria were studied. When FeCl3 was added to a mitochondrial suspension, a pronounced mitochondrial swelling occurred accompanied by the production of lipid peroxide; the two phenomena were closely correlated (r = 0.96, p less than 0.01). idebenone inhibited the mitochondrial swelling and lipid peroxidation in a concentration-dependent manner; the concentration giving 50% inhibition was 37 microM for swelling and 53 microM for lipid peroxidation. Metabolites of idebenone also inhibited the lipid peroxidation. These results suggest that idebenone stabilizes the mitochondrial membrane by inhibiting lipid peroxidation in brain mitochondria.

Schutz E, Wieland E, Hensel A, Niedmann PD,
Dreiss A, Armstrong VW, Schuff-Werner P, Oellerich M.

Abteilung Klinische Chemie,
Georg-August-Universitat, Gottingen, Germany. eschuetz@med.uni-goettingen.de
Clin Biochem 1997 Dec;30(8):619-24

ABSTRACT

OBJECTIVE: Despite the large body of evidence for a major role of neutrophils and oxidant stress, the exact pathogenesis of the early ischemia/reperfusion injury after cold preservation of the liver is not well understood. The potential benefit of an antioxidant on metabolic liver function during reperfusion has been demonstrated in several studies.

MATERIALS AND METHODS: We describe a cold storage/reperfusion damage model with isolated perfused pig livers, where the effects of neutrophils and idebenone, a recently developed benzoquinone antioxidant, were studied. The integrity of sinusoidal endothelial cells (SEC) was estimated by hyaluronic acid concentration in perfusate and the expression of endothelial constitutive nitric oxide synthase (ecNOS) after reperfusion and compared to lipid peroxidation and antioxidant content.

RESULTS: Hyaluronic acid displayed the highest levels and ecNOS mRNA was most depressed in livers reperfused with neutrophils after 20 h cold storage; this was accompanied by an increase in lipid peroxidation (TBARS) and a breakdown of endogenous lipophilic antioxidants (alpha-tocopherol and coenzyme Q-10). These effects were attenuated, when neutrophils were excluded from reperfusion and almost completely abolished by the addition of 200 mumol/L idebenone.

CONCLUSIONS: These data suggest that a leukocyte-mediated damage based on reactive oxygen species markedly contributes to the reperfusion injury of SEC after cold preservation of the liver. Therefore, the presence of effective antioxidants in the early reperfusion phase may be beneficial for liver graft integrity.

Yokoyama H, Tsuchihashi N, Ogata T, Hiramatsu M, Mori N.

Institute for Life Support Technology,
Yamagata Technopolis Foundation, Japan.
MAGMA 1996 Sep-Dec;4(3-4):247-50

ABSTRACT

Electron spin resonance (ESR) measurements after intracerebroventricular injection of a nitroxide radical were carried out in rats (n = 6) that received oral idebenone for 2 weeks and in control rats (n = 5), using an in vivo rapid scan ESR spectrometer. The half-life of nitroxide, which was estimated from the change in the peak height (delta M = +1) of the ESR signals from the head, was used as a marker for the elimination of the nitroxide radical. The half-life in the rats treated with idebenone was significantly shorter than it was in the controls (p < 0.05). This finding indicates that the treatment with idebenone can enhance the intracerebral-eliminating ability of the nitroxide radical.

Esposti MD, Ngo A, Ghelli A, Benelli B,
Carelli V, McLennan H, Linnane AW.

Centre for Molecular Biology and Medicine,
Monash University, Melbourne, Victoria, Australia.
Arch Biochem Biophys 1996 Jun 15;330(2):395-400

ABSTRACT

We have studied the interaction of idebenone with the energy-conserving complexes of the respiratory chain in beef heart mitochondria and compared its energetic efficiency with that of other analogs of coenzyme Q. idebenone is a very effective substrate for succinate:Q reductase and ubiquinol:cytochrome c reductase, but it is clearly a poor substrate for NADH:Q reductase (complex I). Indeed, idebenone is a strong inhibitor of both the redox and proton pumping activity of complex I, showing effects in part similar to those of coenzyme Q-2. However, the mechanism of idebenone interaction with complex I may be different from that of Q-2 because of its different sensitivity to inhibitors. The possible relevance of the present findings to the therapeutic use of idebenone is discussed.

Scavini C, Rozza A, Lanza E,
Favalli L, Racagni G, Brunello N.

Institute of Pharmacology,
University of Pavia, Italy.
Eur Neuropsychopharmacol 1996 May;6(2):95-102

ABSTRACT

The effect of idebenone on the serotonergic system was evaluated in the aging rat by measuring the kinetic constants of 3H-5HT and 3H-ketanserin binding sites in the cerebral cortex of rats at 3, 15 and 24 months of age following acute and subchronic administration of the drug. Idebenone displayed no in vitro affinity toward any population of serotonin receptors and did not modify their kinetic parameters after a single dose of 100 mg/kg, at any age tested. A subchronic treatment with the drug for 21 days at the dose of 30 mg/kg did not induce any relevant change in 3- and 15-month-old rats, whereas it significantly increased the density of both 3H-5HT and 3H-ketanserin binding sites in 24-month-old rats, where a lower number of receptors is detected as a consequence of aging. This effect was rather specific, since under the same experimental conditions no changes were detected in the density of cortical beta-adrenergic receptors in aged animals. In microdialysis studies, acute administration with idebenone did not affect 5HT and 5HIAA release at any age. Conversely, the pattern of serotonin metabolism was significantly modified in aged rats following repeated treatment with idebenone and was partially restored to a value similar to the one observed in young animals. These results suggest that idebenone, a putative neuroprotective agent which has been shown to improve brain metabolism in ischemic conditions, might also attenuate age-associated neuronal damage, acting probably on several neurotransmitter systems which undergo selective modification during aging.

Wieland E, Schutz E, Armstrong VW,
Kuthe F, Heller C, Oellerich M.

Abteilung Klinische Chemie,
Georg-August-Universitat Gottingen, Germany.
Transplantation 1995 Sep 15;60(5):444-51

ABSTRACT

The ability of the benzoquinone coenzyme Q-10 or its derivative idebenone to protect against lipid peroxidation and protein damage mediated by the pro-oxidative system NADPH/ADP/Fe3+ was tested in a rat liver microsomal model incubated in University of Wisconsin (UW) or histidine-tryptophan-ketoglutarate (HTK) solutions. Lipid peroxidation, as followed by direct determination of lipid hydroperoxides and by monitoring of malondialdehyde equivalents, was 1.8-fold enhanced in HTK and 3-fold attenuated in UW compared with HEPES buffer. Function and integrity of microsomal enzymes were investigated using glutathione S-transferase and cytochrome P-450 IIIA activity as assessed by lidocaine N-deethylation to monoethylglycinexylidide as well as by Western blot analysis of the cytochrome P-450 IIIA protein. Glutathione S-transferase activity was reduced by about 70% in HEPES compared with 50% in HTK and 36% in UW. Cytochrome P-450 IIIA was inactivated by about 75% in HEPES and HTK, compared with 55% in UW. The enzyme inactivation was paralleled by a loss of immunoreactive cytochrome P-450 IIIA protein. Supplementation of HTK with 0.1 mumol/L QSA-10 offered complete protection against lipid peroxidation, compared with 100 mumol/L with Q-10. QSA-10 (20 mumol/L) prevented protein damage in both preservation solutions, whereas Q-10 (20 mumol/L) offered only partial protection in UW and had no effect in HTK. The use of QSA-10 (idebenone) during liver transplantation may therefore have the potential of increasing the efficacy of organ preservation, maintaining donor organ quality, and preventing reperfusion injury. It is suitable for human use and has energy-conserving properties in addition to its antioxidant nature.