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.
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Authors | Jin Hee Shin, Sung Ig Cho, Hyang Ran Lim, Jae Keun Lee, Young Ae Lee, Jai Sung Noh, In Soo Joo, Kee-Won Kim, Byoung Joo Gwag |
Journal | Molecular pharmacology
(Mol Pharmacol)
Vol. 71
Issue 4
Pg. 965-75
(Apr 2007)
ISSN: 0026-895X [Print] United States |
PMID | 17105868
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- 2-hydroxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethyl-benzylamino)benzoic acid
- Antioxidants
- Benzoates
- Fluorobenzenes
- Salicylates
- fas Receptor
- meta-Aminobenzoates
- Lithium Carbonate
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Topics |
- Amyotrophic Lateral Sclerosis
(drug therapy, mortality)
- Animals
- Antioxidants
(therapeutic use)
- Apoptosis
(drug effects)
- Benzoates
(administration & dosage, pharmacology)
- Cell Survival
(drug effects)
- Disease Models, Animal
- Drug Therapy, Combination
- Fluorobenzenes
- Lithium Carbonate
(administration & dosage, pharmacology)
- Mice
- Mortality
- Motor Activity
(drug effects)
- Motor Neurons
(drug effects, pathology)
- Oxidative Stress
(drug effects)
- Salicylates
- fas Receptor
(metabolism)
- meta-Aminobenzoates
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