Reactive nitrogen species scavenging, rather than nitric oxide inhibition, protects from articular cartilage damage in rat zymosan-induced arthritis.
1. The contribution of nitric oxide (NO) and peroxynitrite (PN) to inflammation in a zymosan-induced (1 mg, intra-articular, i.art.) rat model of arthritis was assessed by histopathology and by measuring the glycosaminoglycan (GAG) content of the articular cartilage. 2. Progression of the chronic synovitis in zymosan-induced arthritis (ZYA) was associated with increased nitrite and nitrotyrosine (3-NT) levels in the joint exudates that paralleled a progressive loss of the GAG content. An increase in 3-NT was also observed after i.art. PN. 3. The nonselective nitric oxide synthase (NOS) inhibitor l-N(G)-nitroarginine methyl ester (25-75 mg x kg(-1)day(-1)) or the selective inducible NOS inhibitor aminoguanidine (50-100 mg x kg(-1)day(-1)) given 1 h before (prophylactic) or 3 days after (therapeutic) injection of the zymosan ameliorated the synovitis, but worsened the GAG loss, as measured at the end of the experiment (day 7). 4. The PN scavenger uric acid (100-250 mg x kg(-1) i.p. four times daily) given prophylactically until the end of the experiment (day 14), in a dose compatible with its PN scavenging activity, significantly decreased both the synovitis and the GAG loss. 5. In conclusion, PN formation is associated with cartilage damage in addition to proinflammatory activity in ZYA. NOS inhibitors and a PN scavenger were able to reduce the cellular infiltration, while displaying opposite effects on cartilage homeostasis either by enhancing or ameliorating the damage, respectively.
Bezerra
Mirna Marques
MM
Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceará, Fortaleza, Brazil.
Brain
Susan D
SD
Greenacre
Stan
S
Jerônimo
Selma Maria Bezerra
SM
de Melo
Liana Batista
LB
Keeble
Julie
J
da Rocha
Francisco Airton Castro
FA
D000818:Animals; D001169:Arthritis, Experimental / Q000139:chemically induced*; D002358:Cartilage, Articular / Q000187:drug effects* / Q000473:pathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D016166:Free Radical Scavengers / Q000494:pharmacology / Q000627:therapeutic use*; D006025:Glycosaminoglycans / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D006146:Guanidines / Q000494:pharmacology / Q000627:therapeutic use; D007270:Injections, Intra-Articular; D007274:Injections, Intraperitoneal; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D009569:Nitric Oxide / Q000009:adverse effects* / Q000037:antagonists & inhibitors / Q000737:chemistry; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D009573:Nitrites / Q000037:antagonists & inhibitors / Q000737:chemistry; D030421:Peroxynitrous Acid / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D026361:Reactive Nitrogen Species / Q000037:antagonists & inhibitors* / Q000627:therapeutic use; D013582:Synovial Fluid / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D013583:Synovial Membrane / Q000187:drug effects / Q000503:physiopathology / Q000648:ultrastructure; D013585:Synovitis / Q000139:chemically induced / Q000188:drug therapy; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000737:chemistry; D014527:Uric Acid / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology; D015054:Zymosan / Q000008:administration & dosage / Q000009:adverse effects*
D016166:Free Radical Scavengers; D006025:Glycosaminoglycans; D006146:Guanidines; D009573:Nitrites; D026361:Reactive Nitrogen Species; D030421:Peroxynitrous Acid; D014527:Uric Acid; D009569:Nitric Oxide; C002744:3-nitrotyrosine; D014443:Tyrosine; D015054:Zymosan; D019001:Nitric Oxide Synthase; C004479:pimagedine; D019331:NG-Nitroarginine Methyl Ester