Anti-inflammatory effects of specific cyclooxygenase 2,5-lipoxygenase, and inducible nitric oxide synthase inhibitors on experimental autoimmune anterior uveitis (EAAU).
OBJECTIVE
Inflammation, in general, causes the release of a variety of inflammatory mediators that in turn induce cyclooxygenase (COX) 2, nitric oxide synthase (iNOS) and 5-lipoxygense (LP) synthesis, producing large amounts of inflammatory prostaglandins (PG), nitric oxide (NO), and leukotriene (LT) B4. Therefore, inhibition of these enzymes may abrogate intraocular inflammation in experimental autoimmune anterior uveitis (EAAU).


METHODS
Lewis rats were immunized with melanin-associated antigen (MAA) isolated from bovine iris and ciliary body. These animals were divided into three groups. The first group of rats received subcutaneous injection of COX 2 inhibitor CS 236 at different time points. The second and third groups of animals received subcutaneous aminoguanidine (AG), an iNOS inhibitor, and nordihydroguaiaretic acid (NDGA), a 5-LP inhibitor, respectively. Control animals received vehicle. Rat eyes were examined daily by slit-lamp biomicroscopy from Day 7 to 30 post injection for uveitis. Animals were also sacrificed at various time points for histologic analysis.


RESULTS
Control animals developed severe EAAU in both eyes. The disease started in these animals on Day 12 post immunization and lasted for ten days. Interestingly, CS 236, a potent COX 2 inhibitor, completely abrogated EAAU when the animals were treated daily from the Day 0 to 14 or Day 0 to 20 after MAA injection. Furthermore, daily CS 236 treatment after the onset of EAAU (Day 14-20) significantly reduced the severity (both clinical and histologic) of EAAU and shortened the duration of disease. iNOS inhibitor (AG) and 5-LP inhibitor (NDGA) partially attenuated EAAU.


CONCLUSIONS
Our results show that EAAU was partially attenuated by AG and NDGA. Interestingly, CS 236, a potent COX 2 inhibitor, completely inhibited EAAU in male Lewis rats most likely by inhibiting the initial phase and onset of the disease.
Bora
Nalini S
NS
Department of Ophthalmology and Visual Sciences, Kentucky Lions Eye Center, School of Medicine, University of Louisville, 40202, USA. nsbora01@louisville.edu
Sohn
Jeong-Hyeon
JH
Bora
Puran S
PS
Kaplan
Henry J
HJ
Kulkarni
Prasad
P
D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000096:biosynthesis; D001327:Autoimmune Diseases / Q000188:drug therapy* / Q000201:enzymology / Q000276:immunology; D000068579:Celecoxib; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D005500:Follow-Up Studies; D006146:Guanidines / Q000008:administration & dosage / Q000627:therapeutic use; D007279:Injections, Subcutaneous; D016859:Lipoxygenase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D008297:Male; D009637:Masoprocol / Q000008:administration & dosage / Q000627:therapeutic use; D019001:Nitric Oxide Synthase / Q000096:biosynthesis / Q000187:drug effects*; D052247:Nitric Oxide Synthase Type II; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis / Q000187:drug effects*; D011720:Pyrazoles / Q000008:administration & dosage / Q000627:therapeutic use; D051381:Rats; D011917:Rats, Inbred Lew; D013449:Sulfonamides / Q000008:administration & dosage / Q000627:therapeutic use; D016896:Treatment Outcome; D014606:Uveitis, Anterior / Q000188:drug therapy* / Q000201:enzymology / Q000276:immunology
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D006146:Guanidines; D016859:Lipoxygenase Inhibitors; D011720:Pyrazoles; D013449:Sulfonamides; D009637:Masoprocol; D001094:Arachidonate 5-Lipoxygenase; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D000068579:Celecoxib; C004479:pimagedine