Collagen induced arthritis: reversal by mercaptoethylguanidine, a novel antiinflammatory agent with a combined mechanism of action.
OBJECTIVE
We recently identified mercaptoethylguanidine (MEG) as an antiinflammatory agent with a combined mechanism of action. Its effects include inhibition of the inducible isoform of nitric oxide synthase (iNOS), scavenging peroxynitrite, a cytotoxic oxidant species produced from nitric oxide (NO) and superoxide, and inhibition of cyclooxygenase (COX). We investigate the effect of MEG in collagen induced arthritis (CIA).


METHODS
Syngeneic LOU rats were immunized with native type II collagen on Day 0. After clinical signs of arthritis developed on Day 10, treatment with MEG was initiated (30 mg/kg ip tid) and continued until sacrifice on Day 28. Serum nitrite/nitrate was measured in control animals, at arthritis onset and 2 days after the start of MEG treatment. Clinical scores were obtained daily. At Day 28, radiographic scores were obtained, and joints were harvested for the measurement of mRNA for tumor necrosis factor-alpha (TNF-alpha), collagenase, and stromelysin.


RESULTS
Serum nitrite/nitrate increased from 7.9+/-0.7 mM (baseline) to 13.5+/-2.6 at arthritis onset (p < 0.05). Within 48 h of MEG treatment, nitrite/nitrate levels fell to 7.2+/-1.1 (p < 0.05). By Day 28, clinical arthritis scores (measured on a scale of 0-8) were 7.1+/-0.6 in the vehicle group compared to 1.4+/-0.6 in the MEG treated group (p < 0.0001). Radiographic scores (scale 0-6) on Day 28 were reduced from 4.9+/-0.6 to 0.6+/-0.4 (p < 0.0002) by MEG treatment. MEG reduced the synovial expression of mRNA for TNF-alpha, collagenase, and stromelysin by 72, 67, and 52%, respectively.


CONCLUSIONS
These data show that MEG has beneficial effects on established CIA. The mechanism of action may be related to inhibition of synovial iNOS expression or activity, inhibition of COX, scavenging of peroxynitrite, with subsequent inhibition of angiogenesis, metalloproteinase, and TNF-alpha expression.
Brahn
E
E
Division of Rheumatology, UCLA School of Medicine, Los Angeles, CA, USA.
Banquerigo
M L
ML
Firestein
G S
GS
Boyle
D L
DL
Salzman
A L
AL
Szabó
C
C
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001168:Arthritis / Q000139:chemically induced / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000378:metabolism; D003094:Collagen; D017364:Collagenases / Q000378:metabolism; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D006146:Guanidines / Q000494:pharmacology / Q000627:therapeutic use*; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism; D009566:Nitrates / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D009573:Nitrites / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011859:Radiography; D051381:Rats; D013583:Synovial Membrane / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000893:Anti-Inflammatory Agents; D004791:Enzyme Inhibitors; D006146:Guanidines; D009566:Nitrates; D009573:Nitrites; D014409:Tumor Necrosis Factor-alpha; D003094:Collagen; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D011451:Prostaglandin-Endoperoxide Synthases; D017364:Collagenases; D019278:Matrix Metalloproteinase 3; C100078:2-mercaptoethylguanidine