COX-2 inhibition prevents insulin-dependent diabetes in low-dose streptozotocin-treated mice.
Insulin-dependent diabetes mellitus (IDDM) is an autoimmune disease believed to be caused by an inflammatory process in the pancreas leading to selective destruction of the beta cells. Inducible cyclooxygenase (COX-2) is expressed under inflammatory conditions and its product prostaglandin E(2) (PGE(2)) is an important inflammation mediator. We report here that administration of the selective COX-2 inhibitor NS-398 prevents the onset of diabetes in mice brought on by multiple low-doses of streptozotocin (STZ). Histological observations indicated that STZ-mediated destruction of beta cells was prevented by NS-398 treatment. Delayed (day 3) administration of NS-398 was also protective in this model. No protective effect was observed when NS-398 was administered prior to a high, toxic dose of STZ. These results demonstrate the critical importance of COX-2 activity in autoimmune destruction of beta cells, and point to the fact that COX-2 inhibition can potentially develop into a preventive therapy against IDDM.
Tabatabaie
T
T
Free Radical Biology and Aging Research Program, Oklahoma Medical Research Foundation, 825 N. E. 13th Street, Oklahoma City, Oklahoma 73104, USA. Tahereh-Tabatabaie@omrf.ouhsc.edu
Waldon
A M
AM
Jacob
J M
JM
Floyd
R A
RA
Kotake
Y
Y
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000473:pathology / Q000517:prevention & control*; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000473:pathology / Q000517:prevention & control*; D015232:Dinoprostone / Q000378:metabolism; D006442:Glycated Hemoglobin / Q000378:metabolism; D007213:Indomethacin / Q000494:pharmacology; D007527:Isoenzymes / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009578:Nitrobenzenes / Q000008:administration & dosage / Q000494:pharmacology; D010179:Pancreas / Q000187:drug effects / Q000473:pathology; D011451:Prostaglandin-Endoperoxide Synthases / Q000494:pharmacology*; D013311:Streptozocin / Q000008:administration & dosage / Q000633:toxicity; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology; D013997:Time Factors
D001786:Blood Glucose; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D015232:Dinoprostone; D006442:Glycated Hemoglobin; D007213:Indomethacin; D007527:Isoenzymes; D009578:Nitrobenzenes; D011451:Prostaglandin-Endoperoxide Synthases; D013311:Streptozocin; D013449:Sulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide