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SAGE KE Bulletin Board

Eukarion antioxidant efficacy in Flies

31 May 2002

Simon L Melov

The report by Bayne and Sohal in the latest issue of Free Radical Biology and Medicine is interesting due to its negative nature, and overall experimental design. Essentially the report claims that superoxide dismutase catalase mimetics (designed and developed by Eukarion) which extend the lifespan of the nematode C.elegans (1), and reduce protein carbonyl groups in mice (2), do not work in a similar fashion in the housefly musca domestica, and therefore the drugs effects are species specific. There are several salient points which are ommited in the discussion section of the paper by Bayne & Sohal, which directly impact their conclusions, and likely make the overall thrust of the paper incorrect.

1) The compounds developed by Eukarion have poor oral bioavailibility in mammals, and there is no reason to think that this would be better in flies (S. Doctrow, personal communication, Eukarion). In fact, the evidence for the efficacy of the Eukarion antioxidants in relation to oxidative stress comes from a litany of studies demonstrating their efficacy in many animal model systems of oxidative stress (3). This includes the ability of the compounds to reduce the level of protein carbonyl groups (a marker of oxidative damage) in an ALS mouse model (2). The vast majority of published studies using Eukarion compounds, deliver the antioxidants via injection, sub-cutaneous delivery, or for culture experiments, total immersion in a solution of compound.

2) Previous studies showed that the level of carbonyl modifications in mice can be reduced through appropriate administration of the Eukarion antioxidants (2). Bayne & Sohal conclude that as they did not observe a reduction in protein carbonyls in flies which are fed the compounds, this must mean that they are not effective in flies. A more probable explanation is that flies which are fed the compounds simply do not absorb active antioxidant.

3) Further, the observation of toxicity in the flies (via oral delivery of the compounds), is consistent with the antioxidants being broken down in the gut of the flies. Known breakdown products of these compounds, such as ethylenediamine and the salicylaldehydes, are more toxic to cells than the intact compounds. Mammals tolerate high doses of these active compounds when delivered appropriately, i.e. via injection or sub-cutaneous delivery. It is certainly conceivable that potentially toxic, and orally available, breakdown product(s) are, through mechanisms unknown, particularly damaging to the flies subjected to hyperoxic stress. Thus, this toxic effect alone, gives no evidence that intact compound was orally bioavailable in these experiments.

In summary, the entire experimental design is predicated on the belief that the compounds are orally bioavailable in flies, and this belief is not consistent with previous studies in mammals, the vast majority of which rely on intra-venous, intra-peritoneal, or sub-cutaneous delivery of the antioxidants (4). Therefore, the conclusion of the paper should more appropriately be that these type of antioxidants are not orally bioavailable in flies.

Simon Melov Ph.D.
Buck Institute for Age Research
Novato, CA 94945

1) Melov, S., Ravenscroft, J., Malik, S., Gill, M.S., Walker, D.W., Clayton, P.E., Wallace, D.C., Malfroy, B., Doctrow, S.R., and Lithgow, G. Extension of Caenorhabditis elegans lifespan with synthetic superoxide dismutase/catalase mimetics. Science 289:1567-1569, 2000.

2) Jung, C., Rong, Y., Doctrow, S., Baudry, M., Malfroy, B., and Xu, Z. Synthetic superoxidedismutase/catalase mimetics reduce oxidative stress and prolong survival in a mouse amyotrophic lateral sclerosis model. Neuroscience Letters 304: 157-160, 2001.

3)Doctrow, S.R., Adinolfi, C., Baudry, M., Huffman, K., Malfroy, B., Marcus, C.B., Melov, S., Pong, K., Rong, Y., Smart, J., and Tocco, G. Salen manganese complexes, combined superoxide dismutase/catalase mimetics demonstrate potential for treating neurodegenerative and other age- associated diseases. in Oxidative Stress and Aging: Advances in Basic Science, Diagnostics, and Intervention. (H. Rodriguez and R. Cutler, eds.) World Scientific Publishing Company. in press.

4) Melov, S., Doctrow, S.R., Schneider, J.,A., Haberson, J., Patel, M., Coskun, P.E., Huffman, K. Wallace, D.C., and Malfroy, B. Lifespan extension and rescue of neurodegeneration in superoxide dismutase 2 nullizygous mice treated with superoxide dismutase/catalase mimetics. J. Neuroscience, 21: 8348-53, 2001.

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