Effects of idebenone (CV-2619) and its metabolites on respiratory activity and lipid peroxidation in brain mitochondria from rats and dogs.

Sugiyama, Yasuo; Fujita, Toshio; Matsumoto, Mutsuko; Okamoto, Kayoko; Imada, Isuke

doi:10.1248/bpb1978.8.1006

Cited by 54 publications

(25 citation statements)

References 26 publications

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“…Idebenone inhibits the generation of lipid peroxide in rat brain homogenate (63), rat brain mitochondria (62), and dog brain mitochondria (60). We reported that idebenone suppressed lipid peroxide generation in rat brain mitochondria in the presence of NADH, FeC13, and ADP with a 50% inhibitory concentration of 80 p~ (62).…”

Section: Mechanism Of Actionmentioning

confidence: 94%

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Idebenone

Nagaoka

1987

Cardiovascular Drug Reviews

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The increase in the aging population has prompted us to develop new drugs for geriatric diseases. Among these diseases, cerebrovascular lesion (stroke) is one of the major causes of death in many countries. It can cause memory impairment and lead consequently to serious social and medical problems. Basic research findings suggest that biochemical changes and physiological dysfunction of cells damaged by cerebral infarction and hemorrhage can be improved, to some extent, by treating the decreased respiratory function of these cells.Cerebral hemodynamic changes caused by cerebrovascular lesions reduce the supply of nutrients (mainly glucose) and oxygen to the nerve cells and consequently interfere with the cerebral energy metabolism. As cerebral mitochondria are highly sensitive to ischemic conditions, their adenosine triphosphate (ATP) production rapidly decreases. Various cellular brain functions are therefore reduced. The above described changes seem to be basic to cerebrovascular diseases, particularly occlusive cerebrovascular disease, and are closely related to the onset of sequelae. With the aim of activating the function of mitochondria, where cellular energy is produced, various chemical compounds including idebenone were synthesized.To evaluate those newly synthesized compounds, animal models that reflect the above-described pathophysiological changes were needed. We reported the development of stroke-prone spontaneously hypertensive rats (SHR-SP) in 1974 (49). More recently we developed new models of memory impairment, analyzed their characteristics, and tentatively established a system to evaluate drug effects in these animals (25,30,75). Okamoto et al. (50) synthesized a number of benzoquinone compounds. One of them, idebenone, was found to be pharmacologically effective in these models. CHEMISTRYIdebenone (CV-2619), 6-( 1 O-hydroxydecyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone (Fig. l), was synthesized by Imada and co-workers (50)

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Section: Mechanism Of Actionmentioning

confidence: 94%

“…Therefore activating this energyAch (nmol/g) Choliiie 60 producing function of mitochondria stimulates cell function, which in turn may improve cerebral dysfunction caused by cerebrovascular disorders. In fact, idebenone improves energy metabolism and improves neurological symptoms and amnesia associated with cerebral apoplexy.…”

Section: Mechanism Of Actionmentioning

confidence: 99%

Idebenone

Nagaoka

1987

Cardiovascular Drug Reviews

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“…Different sets of biochemical experiments were used to demonstrate that idebenone could protect respiratory function and ameliorate energy metabolism in mitochondria [6,7]. Using mitochondrial assays, researchers also showed that idebenone was rapidly oxidised by mitochondrial complex III and was readily reduced by the ubiquinone reductase function of complex I, as well as by complex II and glyceraldehyde-3-phosphate dehydrogenase [8,9].…”

Section: Idebenone -An Improved Benzoquinonementioning

confidence: 99%

Idebenone: An emerging therapy for Friedreich ataxia

Meier

Buyse

2009

J Neurol

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This paper reviews the history and pre-clinical development of idebenone and summarises the results of clinical studies, published from 1999 to 2008, on the use of idebenone in the treatment of patients with Friedreich ataxia (FRDA). As a benzoquinone that can undergo reversible redox reactions, idebenone influences the electron balance in mitochondria. In vitro studies have shown that it acts both as an anti-oxidant, preventing damage to the mitochondrial membrane, and, more importantly, as an electron carrier, supporting mitochondrial function and adenosine triphosphate (ATP) production. In clinical studies, idebenone has been well tolerated by patients with various pathological conditions. The most common adverse events have been gastrointestinal effects of mild to moderate severity. No neurotoxic or adverse cardiac reactions have been reported in pre-clinical or clinical studies. The good safety profile of idebenone is supported by large clinical trials in Alzheimer's disease and by post-marketing surveillance. Phase 1 studies demonstrated the safety and tolerability of idebenone at relatively high doses (up to 60 mg/kg/day). Results from 11 clinical studies (randomised, controlled, and open-label trials), involving a total of about 200 patients, provide evidence of improvement in both cardiac hypertrophy and neurological symptoms among patients with FRDA treated with idebenone.

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“…Parabenzoquinones such as CoQ 10 and its derivative or analog act by transferring electrons from complex I/II to complex II in the mitochondrial respiratory chain and are thus rapidly reduced [84]. Idebenone was demonstrated to reduce the harmful effects of iron and to protect the heart from iron related injuries [85,86].…”

Section: Antioxidantsmentioning

confidence: 99%

Friedreich’s Ataxia: From the (GAA) n Repeat Mediated Silencing to New Promising Molecules for Therapy

Marmolino

Acquaviva²

2009

Cerebellum

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Friedreich's ataxia (FRDA) is a neurodegenerative disease due to a pathological expansion of a GAA triplet repeat in the first intron of the FXN gene encoding for the mitochondrial protein frataxin. The expansion is responsible for most cases of FRDA through the formation of a nonusual B-DNA structure and heterochromatin conformation that determine a direct transcriptional silencing and the subsequent reduction in frataxin expression. Among other functions, frataxin is an iron chaperone central for the assembly of iron-sulfur clusters in mitochondria; its reduction is associated with iron accumulation in mitochondria, increased cellular sensitivity to oxidative stress and cell damage. There is, nowadays, no effective therapy for FRDA and current therapeutic strategies mainly act to slow down the consequences of frataxin deficiency. Therefore, drugs that are able to increase the amount of frataxin are excellent candidates for a rational approach to FRDA therapy. Recently, several drugs have been assessed for their ability to increase the amount of cellular frataxin, including human recombinant erythropoietin, histone deacetylase inhibitors, and the PPAR-gamma agonists.

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Effects of idebenone (CV-2619) and its metabolites on respiratory activity and lipid peroxidation in brain mitochondria from rats and dogs.

Cited by 54 publications

References 26 publications

Idebenone

Idebenone

Idebenone: An emerging therapy for Friedreich ataxia

Friedreich’s Ataxia: From the (GAA) n Repeat Mediated Silencing to New Promising Molecules for Therapy

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