Cyclooxygenase 2 inhibition protects motor neurons and prolongs survival in a transgenic mouse model of ALS.
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.
Drachman
Daniel B
DB
Departments of Neurology and Neuroscience, Johns Hopkins University School of Medicine, Meyer 6-109, 600 N. Wolfe Street, Baltimore, MD 21287-7519, USA.
Frank
Krystl
K
Dykes-Hoberg
Margaret
M
Teismann
Peter
P
Almer
Gabrielle
G
Przedborski
Serge
S
Rothstein
Jeffrey D
JD
D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics*; D000818:Animals; D000068579:Celecoxib; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D015232:Dinoprostone / Q000037:antagonists & inhibitors / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000187:drug effects* / Q000201:enzymology* / Q000473:pathology; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011720:Pyrazoles; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use; D015996:Survival Rate
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D008565:Membrane Proteins; D011720:Pyrazoles; D013449:Sulfonamides; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D000068579:Celecoxib; D015232:Dinoprostone