Clopidogrel, a P2Y12 Receptor Antagonist, Potentiates the Inflammatory Response in a Rat Model of Peptidoglycan Polysaccharide - Induced Arthritis,

Abstract

Abstract 3287Clopidogrel is a widely used anti-thrombotic drug that prevents platelet activation by irreversibly antagonizing P2Y12 receptor. This drug could be co-administrated in patients afflicted with inflammatory conditions, such as rheumatoid arthritis and lupus. Hence it is of importance to determine if blocking P2Y12 receptors has any therapeutic benefit during the inflammatory response. Therefore, we evaluated the effect of clopidogrel using an animal model of chronic inflammation. Genetically susceptible Lewis rats were injected intraperitoneally with peptidoglycan polysaccharide (PGPS) to develop arthritis and followed for 21 days. Interestingly, we noticed an increased level of inflammation in induced arthritis animals treated with clopidogrel compared with induced arthritis animals alone, including a) increased in joint diameter between day 15 and 21 (p<0.0001) with augmented clinical manifestations of inflammation, b) an elevated neutrophil blood count and an increased circulating platelet count (926 ± 195 × 103 vs. 561.25 ± 97 × 103 mL; p<0.05). Furthermore, microscopic differences were observed at the site of joint inflammation namely: a significant increase in leukocyte infiltration, pannus formation, blood vessel proliferation, subsynovial fibrosis and cartilage erosion upon treatment with clopidogrel in induced arthritis animals. Plasma levels of pro-inflammatory cytokines, namely IL-1 beta, interferon (IFN) gamma, and IL-6, were significantly increased in the induced arthritis animals treated with clopidogrel when compared to induced arthritis animals alone (p<0.05). In contrast, plasma levels of IL-10 were significantly lower when animals were treated with clopidogrel compared to induced arthritis animals alone (p<0.05). Plasma levels of platelet factor 4 (PF4) were increased in all animals treated with PGPS, however PF4 levels show not difference with clopidogrel treatment. This last finding suggests that the pro- inflammatory effect of clopidogrel may be due to its action on cells other than platelets. In summary, according to clinical observations, histopathology measurements and cytokine results, the antagonism of the P2Y12 receptor has a pro-inflammatory effect in this model of erosive arthritis, which might not be mediated only by platelets. These data provide new insights into the role that thienopyridine metabolites play during chronic inflammation distant from their action on platelets and with a detrimental outcome in this model of erosive arthritis Disclosures:No relevant conflicts of interest to declare.