Brain distribution of idebenone and its effect on local cerebral glucose utilization in rats

Nagai, Yasuo; Yoshida, Kiyoshi; Narumi, Shigehiko; Tanayama, Shigeharu; Nagaoka, Akinobu

doi:10.1016/0167-4943(89)90008-3

Cited by 37 publications

(18 citation statements)

References 16 publications

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“…Idebenone is a short chain analogue of coenzyme Q 10 , is well tolerated by humans, crosses the blood brain barrier [46], has been reported to be a relatively good antioxidant [45], and has been used in a variety of diseases with some benefits [25,50]. The effect of idebenone upon cardiac hypertrophy in FRDA patients was assessed using echocardiography.…”

Section: Antioxidant Therapymentioning

confidence: 99%

Friedreich's Ataxia: Disease mechanisms, antioxidant and Coenzyme Q₁₀ therapy

Cooper

Schapira

2003

BioFactors

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Mitochondria clearly play a central role in the pathogenesis of Friedreich's Ataxia. The most common genetic abnormality results in the deficiency of the protein frataxin, which is targeted to the mitochondrion. Research since this discovery has indicated that mitochondrial respiratory chain dysfunction, mitochondrial iron accumulation and oxidative damage are important components of the disease mechanism. While the role of frataxin is not known, evidence is currently pointing to a role in either mitochondrial iron handling or iron sulphur centre synthesis. These advances in our understanding of the disease mechanisms are enabling therapeutic avenues to be explored, in particular the use of established drugs such as antioxidants and enhancers of respiratory chain function. Vitamin E therapy has been shown to be beneficial in patients with ataxia with vitamin E deficiency, and CoQ10 therapy was effective in some patients with ataxia associated with CoQ10 deficiency. A combined therapy involving long term treatment with high doses of vitamin E and coenzyme Q10 has jointly targeted two of the major features of Friedreich's Ataxia; decreased mitochondrial respiratory chain function and increased oxidative stress. This therapy clearly showed a rapid and sustained increase in the energy generated by the FRDA heart muscle, nearly returning to normal levels. The improvements in skeletal muscle energy generation parallel those of the heart but to a lower level. While this therapy appeared to slow the predicted progression of some clinical symptoms a larger placebo controlled study is required to confirm these observations. Other antioxidant strategies have involved the use of Idebenone, selenium and N acetyl cysteine but only the use of Idebenone has involved structured trials with relatively large patient numbers. Idebenone clearly had an impact upon the cardiac hypertrophy in the majority of patients, although there have not been any other significant benefits reported to date.

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Section: Antioxidant Therapymentioning

confidence: 99%

Friedreich's Ataxia: Disease mechanisms, antioxidant and Coenzyme Q₁₀ therapy

Cooper

Schapira

2003

BioFactors

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“…14 C radiolabelling experiments established that idebenone crosses the blood-brain barrier following oral administration [16,17]. Idebenone protects against neuronal death caused by α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptor stimulation in vitro [18] and in vivo [19].…”

Section: Introductionmentioning

confidence: 99%

Idebenone and neuroprotection: antioxidant, pro-oxidant, or electron carrier?

Jaber

Polster

2014

J Bioenerg Biomembr

111

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Ubiquinone, commonly called coenzyme Q10 (CoQ), is a lipophilic electron carrier and endogenous antioxidant found in all cellular membranes. In the mitochondrial inner membrane it transfers electrons to complex III of the electron transport chain. The short chain CoQ analogue idebenone is in clinical trials for a number of diseases that exhibit a mitochondrial etiology. Nevertheless, evidence that idebenone ameliorates neurological symptoms in human disease is inconsistent. Although championed as an antioxidant, idebenone can also act as a pro-oxidant by forming an unstable semiquinone at complex I. The antioxidant function of idebenone is critically dependent on two-electron reduction to idebenol without the creation of unstable intermediates. Recently, cytoplasmic NAD(P)H:quinone oxidoreductase 1 (NQO1) was identified as a major enzyme catalyzing idebenone reduction. While reduction allows idebenone to act as an antioxidant, evidence also suggests that NQO1 enables idebenone to shuttle reducing equivalents from cytoplasmic NAD(P)H to mitochondrial complex III, bypassing any upstream damage to the electron transport chain. In this mini-review we discuss how idebenone can influence mitochondrial function within the context of cytoprotection. Importantly, in the brain NQO1 is expressed primarily by glia rather than neurons. As NQO1 is an inducible enzyme regulated by oxidative stress and the nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE) pathway, optimizing NQO1 expression in appropriate cell types within a specific disease context may be key to delivering on idebenone's therapeutic potential.

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“…Idebenone, a short-chain analog of CoQ-10, crosses the bloodbrain barrier [9], and has been reported to be a relatively good antioxidant [10] and to improve mitochondrial ATP production in the Fig. 1.…”

Section: Discussionmentioning

confidence: 99%