Clopidogrel, a P2Y12 Receptor Antagonist, Potentiates the Inflammatory Response In An Animal Model of Erosive Arthritis

Abstract 4721

The P2Y12 receptor plays a crucial role in the regulation of platelet activation by several agonists. The active metabolite of clopidogrel, a widely used anti-thrombotic drug, irreversibly antagonizes the P2Y12 receptor. However, treatment with clopidogrel has been associated with joint inflammation. In addition, Boilard E. et al identified micro-particles generated by activated platelets in joint fluid from rheumatoid arthritis (RA) patients. In this study we investigated whether platelet activation leads to changes in inflammatory responses using a rat model of erosive arthritis. Here, we evaluated the effect of clopidogrel on inflammation in Lewis rats in a peptidoglycan polysaccharide (PG-PS)-induced arthritis model with four groups of eight rats each: untreated group, animals receiving clopidogrel (clopidogrel group), animals receiving PG-PS (PG-PS group), and animals receiving PG-PS as well as clopidogrel (PG-PS + clopidogrel group). There were significant differences between the PG-PS + clopidogrel treated group when compared to PG-PS treated group including: increased joint diameter [4.24 ± 0.73 vs. 2.70 ± 1.09; p<0.05], clinical manifestations of inflammation, elevated leukocytes count [14.19 ± 0.2 K/uL vs. 9.7 ± 1.4 K/uL; p<0.05] at the expense of neutrophils, increased platelet count [926 ± 195 K/uL vs. 561.25 ± 97 K/uL; p>0.05], and elevated plasma levels of pro-inflammatory cytokines such as IL-1beta, IF gamma, IL-6. Plasma levels of anti-inflammatory cytokine IL-10 were significantly lower in PG-PS + clopidogrel treated group compared to PG-PS group alone. Histological observations indicated an increase in leukocyte infiltration at the inflammatory area of the joint, increased pannus formation and decrease in bone mass upon treatment with clopidogrel in PG-PS-induced arthritis animals. Accordingly to the clinical, histological and cytokine results, we conclude that clopidogrel has a pro-inflammatory effect in PG-PS-induced arthritis animal model and this might implicate that P2Y12 receptor antagonism might enhance inflammatory responses.