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Cyclooxygenase 2 inhibition protects motor neurons and prolongs survival in a transgenic mouse model of ALS
Author(s) -
Drachman Daniel B.,
Frank Krystl,
DykesHoberg Margaret,
Teismann Peter,
Almer Gabrielle,
Przedborski Serge,
Rothstein Jeffrey D.
Publication year - 2002
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.10374
Subject(s) - astrogliosis , cyclooxygenase , excitotoxicity , prostaglandin e2 , amyotrophic lateral sclerosis , genetically modified mouse , proinflammatory cytokine , celecoxib , pharmacology , eicosanoid , glutamate receptor , apoptosis , chemistry , medicine , programmed cell death , transgene , arachidonic acid , inflammation , biochemistry , central nervous system , disease , enzyme , receptor , gene
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. Ann Neurol 2002