Abstract
The pathogenesis of cell death in amyotrophic lateral sclerosis (ALS) may involve glutamate-mediated excitotoxicity, oxidative damage, and apoptosis. We used a transgenic mouse model of ALS to determine the effect of inhibition of cyclooxygenase-2 in treating the disease. Cyclooxygenase-2, present in spinal neurons and astrocytes, catalyzes the synthesis of prostaglandin E2. Prostaglandin E2 stimulates glutamate release from astrocytes, whereas cyclooxygenase-2 also plays a key role in the production of proinflammatory cytokines, reactive oxygen species, and free radicals. Treatment with a selective cyclooxygenase-2 inhibitor, celecoxib, markedly inhibited production of prostaglandin E2 in the spinal cords of ALS mice. Celecoxib treatment significantly delayed the onset of weakness and weight loss and prolonged survival by 25%. Spinal cords of treated ALS mice showed significant preservation of spinal neurons and diminished astrogliosis and microglial activation. Our results suggest that cyclooxygenase-2 inhibition may benefit ALS patients.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Amyotrophic Lateral Sclerosis / drug therapy
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Amyotrophic Lateral Sclerosis / enzymology*
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Amyotrophic Lateral Sclerosis / genetics*
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Animals
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Celecoxib
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Cyclooxygenase 2
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Cyclooxygenase 2 Inhibitors
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Cyclooxygenase Inhibitors / pharmacology*
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Cyclooxygenase Inhibitors / therapeutic use
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Dinoprostone / antagonists & inhibitors
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Dinoprostone / metabolism
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Disease Models, Animal*
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Female
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Humans
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Isoenzymes / antagonists & inhibitors*
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Isoenzymes / metabolism
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Male
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Membrane Proteins
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Mice
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Mice, Transgenic
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Motor Neurons / drug effects*
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Motor Neurons / enzymology*
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Motor Neurons / pathology
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Prostaglandin-Endoperoxide Synthases / metabolism
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Pyrazoles
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Sulfonamides / pharmacology
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Sulfonamides / therapeutic use
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Survival Rate
Substances
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Cyclooxygenase 2 Inhibitors
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Cyclooxygenase Inhibitors
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Isoenzymes
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Membrane Proteins
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Pyrazoles
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Sulfonamides
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Cyclooxygenase 2
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PTGS2 protein, human
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Prostaglandin-Endoperoxide Synthases
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Celecoxib
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Dinoprostone