Part II: beneficial effects of the peroxynitrite decomposition catalyst FP15 in murine models of arthritis and colitis.
BACKGROUND
Peroxynitrite is a reactive oxidant species produced from nitric oxide and superoxide, which has been indirectly implicated in the pathogenesis of many inflammatory conditions including arthritis and colitis. Here, using a novel peroxynitrite decomposition catalyst, FP15, we directly investigate the role of peroxynitrite in the pathogenesis of arthritis and colitis in rodent models.


METHODS
Arthritis was induced in mice by intradermal collagen injection; incidence and severity of arthritis was monitored using a macroscopic scoring system. At the end of the experiment paws were taken for determination of neutrophil infiltration (myeloperoxidase [MPO] activity), oxidative stress (malondialdehyde [MDA] level), and cytokine/chemokine levels. Colitis was induced in mice by 5% dextran sodium sulfate (DSS) in their drinking water. Colitis symptoms were assessed 10 days later, the parameters determined included body weight, rectal bleeding, colon length, colonic MPO and MDA levels, and colon histologic damage.


RESULTS
Treatment with FP15 significantly reduced the inflammation and oxidative stress in arthritis and colitis. FP15 reduced both the incidence and severity of arthritis in mice and this was associated with reduced paw MPO and MDA levels. Similarly, in colitis, FP15 reduced colon damage, and this was associated with reduced colon neutrophil infiltration and oxidative stress.


CONCLUSIONS
The protective effect of FP15 suggests that peroxynitrite plays a significant pathogenetic role in arthritis and colitis in the currently employed rodent models. Further work is needed to determine whether neutralization of peroxynitrite also represents a promising strategy to treat human inflammatory diseases such as arthritis and colitis.
Mabley
Jon G
JG
Inotek Pharmaceuticals Corporation, Cummings Center, Beverly, Massachusetts 01905, USA.
Liaudet
Lucas
L
Pacher
Pál
P
Southan
Garry J
GJ
Groves
John T
JT
Salzman
Andrew L
AL
Szabó
Csaba
C
D000284:Administration, Oral; D000818:Animals; D001168:Arthritis / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D002384:Catalysis / Q000187:drug effects; D003092:Colitis / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D003106:Colon / Q000187:drug effects / Q000473:pathology; D004195:Disease Models, Animal; D008297:Male; D008665:Metalloporphyrins / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D030421:Peroxynitrous Acid / Q000378:metabolism*; D013997:Time Factors
C471469:FeCl tetrakis-2-(triethyleneglycolmonomethylether)pyridylporphyrin; D008665:Metalloporphyrins; D030421:Peroxynitrous Acid