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Concurrent administration of Neu2000 and lithium produces marked improvement of motor neuron survival, motor function, and mortality in a mouse model of amyotrophic lateral sclerosis.

Authors
Shin, JH; Cho, SI; Lim, HR; Lee, JK; Lee, YA; Noh, JS; Joo, IS; Kim, KW; Gwag, BJ
Citation
Molecular pharmacology, 71(4):965-975, 2007
Journal Title
Molecular pharmacology
ISSN
0026-895X1521-0111
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.
MeSH terms
Amyotrophic Lateral Sclerosis/drug therapy*Amyotrophic Lateral Sclerosis/mortalityAnimalsAntigens, CD95/metabolismAntioxidants/therapeutic useApoptosis/drug effectsBenzoic Acids/administration & dosage*Benzoic Acids/pharmacologyCell Survival/drug effectsDisease Models, AnimalDrug Therapy, CombinationLithium Carbonate/administration & dosage*Lithium Carbonate/pharmacologyMiceMortalityMotor Activity/drug effectsMotor Neurons/drug effectsMotor Neurons/pathologyOxidative Stress/drug effects
DOI
10.1124/mol.106.030676
PMID
17105868
Appears in Collections:
Journal Papers > School of Medicine / Graduate School of Medicine > Pharmacology
Journal Papers > Research Organization > Research Institute for Neural Science & Technology
Journal Papers > School of Medicine / Graduate School of Medicine > Psychiatry & Behavioural Sciences
Journal Papers > School of Medicine / Graduate School of Medicine > Neurology
AJOU Authors
조, 성익노, 재성주, 인수곽, 병주
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