Additive neuroprotective effects of creatine and cyclooxygenase 2 inhibitors in a transgenic mouse model of amyotrophic lateral sclerosis.
There is substantial evidence implicating both inflammation and mitochondrial dysfunction in amyotrophic lateral sclerosis (ALS) pathogenesis. We investigated the therapeutic effects of cyclooxygenase 2 (COX-2) inhibitors both alone and in combination with creatine in the G93A transgenic mouse model of ALS. Oral administration of either celecoxib or rofecoxib significantly improved motor performance, attenuated weight loss and extended survival. The administration of COX-2 inhibitors significantly reduced prostaglandin E2 levels at 110 days of age. The combination of creatine with COX-2 inhibitors produced additive neuroprotective effects and extended survival by approximately 30%. The COX-2 inhibitors significantly protected against depletion of anterior horn motor neurons and creatine with COX-2 inhibitors showed greater protection than COX-2 inhibitors alone. These results suggest that combinations of therapies targeting different disease mechanisms may be a useful strategy in the treatment of ALS.
Klivenyi
Peter
P
Department of Neurology and Neuroscience, New York Presbyterian Hospital-Weill Medical College of Cornell University, New York, New York 10021, USA.
Kiaei
Mahmoud
M
Gardian
Gabrielle
G
Calingasan
Noel Y
NY
Beal
M Flint
MF
D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D003401:Creatine / Q000494:pharmacology / Q000627:therapeutic use*; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005260:Female; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D013482:Superoxide Dismutase / Q000096:biosynthesis / Q000235:genetics
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D018696:Neuroprotective Agents; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; C109415:SOD1 G93A protein; D013482:Superoxide Dismutase; D003401:Creatine