Abstract
The Fas pathway and oxidative stress mediate neuronal death in stroke and may contribute to neurodegenerative disease. We tested the hypothesis that these two factors synergistically produce spinal motor neuron degeneration in amyotrophic lateral sclerosis (ALS). Levels of reactive oxygen species were increased in motor neurons from ALS mice compared with wild-type mice at age 10 weeks, before symptom onset. The proapoptotic proteins Fas, Fas-associated death domain, caspase 8, and caspase 3 were also elevated. Oral administration of 2-hydroxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethyl-benzylamino)-benzoic acid (Neu2000), a potent antioxidant, blocked the increase in reactive oxygen species but only slightly reduced activation of proapoptotic proteins. Administration of lithium carbonate (Li+), a mood stabilizer that prevents apoptosis, blocked the apoptosis machinery without preventing oxidative stress. Neu2000 or Li+ alone significantly enhanced survival time and motor function and together had an additive effect. These findings provide evidence that jointly targeting oxidative stress and Fas-mediated apoptosis can prevent neuronal loss and motor dysfunction in ALS.
Footnotes
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This work was supported by grants from the Brain Research Center (M103KV010016 04K2201 01610) of the 21st Century Frontier Research Program, funded by the Ministry of Science and Technology (to B.J.G.) and the Driving Force Project for the Next Generation of Gyeonggi Provincial Government in the Republic of Korea (to S.I.C., J.S.N., B.J.G.).
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Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.
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doi:10.1124/mol.106.030676.
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ABBREVIATIONS: ALS, amyotrophic lateral sclerosis; PaGE, paw grip endurance; MFR, mitochondrial free radicals; DIV, days in vitro; BSO, dl-buthionine-[S,R]-sulfoximine; SOD, superoxide dismutase; LDH, lactate dehydrogenase; FADD, Fas-associated death domain.
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↵ The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.
- Received September 12, 2006.
- Accepted November 10, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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