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Author response to “Reply to Drug Insight: antioxidant therapy in inherited ataxias”

Response to: Gohil K and Azzi A (2008) Reply to Drug Insight: antioxidant therapy in inherited ataxias. Nat Clin Pract Neurol 4: E1 doi:10.1038/ncpneuro0833

Arising from: Pandolfo M (2008) Drug Insight: antioxidant therapy in inherited ataxias. Nat Clin Pract Neurol 4: 86–96 doi:10.1038/ncpneuro0704

Gohil and Azzi challenge the statement “the pathogenesis of ataxia with vitamin E deficiency (AVED) is directly related to impaired antioxidant defenses”, which I made in my Review on the use of antioxidants in the treatment of hereditary ataxias.1 To support their claim, they quote several papers—including recent work published after my Review was completed—suggesting that markers of oxidative stress are not found in affected tissues in mouse models of vitamin E deficiency, and they question whether markers of oxidative stress have ever been detected in patients with AVED.

A Medline search using the terms “vitamin E deficiency” and “oxidative stress” returned 196 citations as of 10 March 2008. Most of these references include statements defining vitamin E as an antioxidant and describe markers of oxidative damage in various cellular and animal models of vitamin E deficiency. In particular, the first report of knock-out mice for α-tocopherol transfer protein demonstrates increased levels of lipid peroxidation in these mice.2 The same paper reports that when these animals were treated with α-tocopherol, their neurological phenotype improved and levels of lipid peroxidation markers decreased. The contradictory findings cited by Gohil and Azzi, as well as similar findings in other work—for example, Hermans et al.,3 who did not detect increased levels of lipid peroxidation markers in rats after 20 weeks of a vitamin-deficient diet—do not exclude an antioxidant role for vitamin E, or oxidative stress as a consequence of its deficiency. The importance of compensatory responses and other changes induced by deficiency of a single factor in complex systems, which Hermans et al. highlighted in their paper, cannot be overstated. Frataxin deficiency also results in decreased markers of oxidative stress in a conditional knock-out mouse model,4 a result defined as “paradoxical” even by the authors of the paper and clearly at odds with findings in other models of the disease and in patients with Friedreich ataxia. In addition, as is the case for frataxin, vitamin E may have additional functional roles that are not limited to antioxidant mechanisms and that are currently poorly understood. The controversies in this field were demonstrated by the back-to-back publication, in Free Radical Biology and Medicine, of two reviews presenting completely opposite points of view.5,6 The same issue of the journal featured a commentary7 that discussed the strengths and weaknesses of both arguments in a balanced manner, and invited researchers to contribute to the debate.

As regards my article, clearly these issues could not be dealt with in detail in a general Review on antioxidant treatments in hereditary ataxias. I consider that the statement that AVED results from impaired antioxidant mechanisms accurately reflects the conclusions that can be drawn from a review of the literature, without denying that actual mechanisms and responses are indeed complex and might lead to paradoxical results in some situations. In practice, administration of vitamin E, a molecule overwhelmingly defined as an antioxidant in the biomedical literature, is an effective treatment for most patients with AVED.


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  2. 2

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    Brigelius-Flohé R and Davis KJA (2007) Is vitamin E an antioxidant, a regulator of signal transduction and gene expression, or a 'junk' food? Comments on the two accompanying papers: “Molecular mechanism of α-tocopherol action” by A. Azzi and “Vitamin E, antioxidant and nothing more” by M. Traber and J. Atkinson. Free Radic Biol Med 43: 2–3

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M Pandolfo has acted as a consultant for Santhera and Takeda, and has received honoraria from Takeda.

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Pandolfo, M. Author response to “Reply to Drug Insight: antioxidant therapy in inherited ataxias”. Nat Rev Neurol 4, E2 (2008).

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