Protective effects of Fe-Aox29, a novel antioxidant derived from a molecular combination of Idebenone and vitamin E, in immortalized fibroblasts and fibroblasts from patients with Friedreich Ataxia

Jauslin, Matthias L.; Vertuani, Silvia; Durini, Elisa; Buzzoni, Lisa; Ciliberti, Nunzia; Verdecchia, Sara; Palozza, Paola; Meier, Thomas; Manfredini, Stefano

doi:10.1007/s11010-007-9429-2

Cited by 17 publications

(20 citation statements)

References 35 publications

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“…Moreover, other studies have found increased plasma and urinary levels of oxidative stress markers in FRDA patients [13][14][15][16][17] and have demonstrated that some antioxidants, such as idebenone and vitamin E, might have a protective role [18,19].…”

Section: Introductionmentioning

confidence: 98%

Friedreich's ataxia: Oxidative stress and cytoskeletal abnormalities

Sparaco

Gaeta

Santorelli

et al. 2009

Journal of the Neurological Sciences

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Section: Introductionmentioning

confidence: 98%

Friedreich's ataxia: Oxidative stress and cytoskeletal abnormalities

Sparaco

Gaeta

Santorelli

et al. 2009

Journal of the Neurological Sciences

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“…34,35 The cells were subjected to L-buthionine (S,R)-sulfoximine (BSO), an inhibitor of de novo glutathione (GSH) biosynthesis. 36 The half-maximal effective concentrations (EC 50 ) were determined (Table 1).…”

mentioning

confidence: 99%

“…Oxidative damage-induced death of FRDA fibroblasts was blocked by exogenous antioxidants. 34,35 Compound 6, 7, and 9 were by far the most efficient, having EC 50 values of 22 ± 7, 25 ± 4, and 32 ± 4 nM, respectively (Table 1). Again, in this assay the optimal side chain length was between 14 and 16 atoms.…”

mentioning

confidence: 99%

An Optimized Pyrimidinol Multifunctional Radical Quencher

Khdour

Arce

Roy

et al. 2013

ACS Med. Chem. Lett.

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A series of aza analogues (4−9) of the experimental neuroprotective drug idebenone (1) have been prepared and evaluated for their ability to attenuate oxidative stress induced by glutathione depletion and to compensate for the decrease in oxidative phosphorylation efficiency in cultured Friedreich's ataxia (FRDA) fibroblasts and lymphocytes and also coenzyme Q 10 -deficient lymphocytes. Modification of the redox core of the previously reported 3 improved its antioxidant and cytoprotective properties. Compounds 4−9, having the same redox core, exhibited a range of antioxidant activities, reflecting side chain differences. Compounds having side chains extending 14−16 atoms from the pyrimidinol ring (6, 7, and 9) were potent antioxidants. They were superior to idebenone and more active than 3, 4, 5, and 8. Optimized analogue 7 and its acetate (7a) are of interest in defining potential therapeutic agents capable of blocking oxidative stress, maintaining mitochondrial membrane integrity, and augmenting ATP levels. Compounds with such properties may find utility in treating mitochondrial and neurodegenerative diseases such as FRDA and Alzheimer's disease. KEYWORDS: Mitochondrial dysfunction, electron transport chain, lipid peroxidation, cytoprotection, adenosine triphosphate M itochondrial dysfunction is linked to numerous neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, Huntington's disease, and Friedreich's ataxia.1−6 Mitochondria are vitally important organelles involved in many essential cellular functions, notably energy metabolism. They produce 90% of our cellular ATP through oxidative phosphorylation within the mitochondrial respiratory chain.7−11 Within mitochondria, the primary site of reactive oxygen species (ROS) generation is the electron transport chain; 12,13 normally, mitochondria have an extensive network of antioxidant and detoxification systems, ensuring that lipid peroxidation and levels of ROS are kept at physiologically acceptable levels.14,15 Defects in the mitochondrial respiratory chain can undoubtedly lead to increased electron leakage and consequently to increased ROS production, causing progressive oxidative damage and ultimately cell death. 2−5,10,16The antioxidant and bioenergetic effects of coenzyme Q (CoQ 10 ) are well-known, 17,18 but its clinical utility is limited by its extreme hydrophobicity, which results in low bioavaibility. 19,20 To facilitate the delivery of such molecules to the mitochondria of cells, we have designed antioxidants bearing smaller lipophilic side chains and having pyrimidinol 21 or pyridinol 22−26 redox cores, based on earlier studies. 27−30 We demonstrated that an aza analogue of idebenone (3, Figure 1), having the 1,4-benzoquinone core replaced with a pyrimidinol core, retained the ability to function within the mitochondria. 21Because these aza analogues function at a number of levels to suppress damage that would otherwise be caused by electron leakage from the electron transport chain, we have denoted them multifunct...

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“…Notably, the antioxidant effect of idebenone in several studies was enhanced in presence of complex II substrates [25,26], suggesting that the antioxidant effect of idebenone is dependent on the reduced form of the molecule, a hypothesis that was later experimentally confirmed [27]. In line with its antioxidative activity, idebenone increased viability of glutathione (GSH)-depleted cells [28][29][30][31]. Moreover, in an ex vivo model of staurosporin-stressed retinal neurons, idebenone normalized mitochondrial and cytoplasmic ROS levels in these cells and prevented the associated cell death [32].…”

Section: Pharmacodynamicsmentioning

confidence: 89%