Erosive Arthritis and Hepatic Granuloma Formation Induced by Peptidoglycan Polysaccharide in Rats Is Aggravated by Prasugrel Treatment

Abstract

Administration of the thienopyridine P2Y12 receptor antagonist, clopidogrel, increased the erosive arthritis induced by peptidoglycan polysaccharide (PG-PS) in rats or by injection of the arthritogenic K/BxN serum in mice. To determine if the detrimental effects are caused exclusively by clopidogrel, we evaluated prasugrel, a third-generation thienopyridine pro-drug, that contrary to clopidogrel is mostly metabolized into its active metabolite in the intestine. Prasugrel effects were examined on the PG-PS-induced arthritis rat model. Erosive arthritis was induced in Lewis rats followed by treatment with prasugrel for 21 days. Prasugrel treated arthritic animals showed a significant increase in the inflammatory response, compared with untreated arthritic rats, in terms of augmented macroscopic joint diameter associated with significant signs of inflammation, histomorphometric measurements of the hind joints and elevated platelet number. Moreover, fibrosis at the pannus, assessed by immunofluorescence of connective tissue growth factor, was increased in arthritic rats treated with prasugrel. In addition to the arthritic manifestations, hepatomegaly, liver granulomas and giant cell formation were observed after PG-PS induction and even more after prasugrel exposure. Cytokine plasma levels of IL-1 beta, IL-6, MIP1 alpha, MCP1, IL-17 and RANTES were increased in arthritis-induced animals. IL-10 plasma levels were significantly decreased in animals treated with prasugrel. Overall, prasugrel enhances inflammation in joints and liver of this animal model. Since prasugrel metabolites inhibit neutrophil function ex-vivo and the effects of both clopidogrel and prasugrel metabolites on platelets are identical, we conclude that the thienopyridines metabolites might exert non-platelet effects on other immune cells to aggravate inflammation.

Aspirin and P2Y12 Inhibitors in platelet-mediated activation of neutrophils and monocytes

“…Aspirin-induced COX inhibition enhances the generation of anti-inflammatory lipoxins, such as 15-epi-lipoxin, which has protective effects on post-ischemic hyperperfusion and lung injury (46,75). P2Y 12 is also found on other cell types (76), and exerts non-platelet mediated pro-and anti-inflammatory ef-fects on leukocytes (77,78) and mediates leukocyte migration in transplant arteriosclerosis independently of platelet P2Y 12 (79). The effect of aspirin and P2Y 12 inhibitors on leukocyte functions further seems to depend on the pathological condition of the patient or on the disease models as effects observed in healthy volunteers are not always reflected by patient cohorts (80).…”

Secreted folate receptor γ drives fibrogenesis in metabolic dysfunction–associated steatohepatitis by amplifying TGFβ signaling in hepatic stellate cells

“…Forty-eight hours after the last dose, animals were euthanized, plasma was separated, and liver tissue was extracted as described above. Blood cell counts were determined using the Hemavet automatic counter, following the previously established protocol ( 62 , 63 ). Liver samples were rapidly frozen and embedded in optimal cutting temperature compound.…”

The Signaling Pathway of the ADP Receptor P2Y12 in the Immune System: Recent Discoveries and New Challenges

“…It is also noted that the majority of the patients were women [ 120 ]. In contrast with all the inflammation models previously reported, our group showed that, during erosive arthritis induced by peptidoglycan polysaccharide, the severity of the inflammation in the joints was augmented when animals were pre-treated with clopidogrel [ 15 ] or prasugrel [ 121 ]. This discrepancy between studies suggests that more investigations need to be carried out to understand how P2Y 12 antagonism can alter RA and to determine whether P2Y 12 antagonist exerts beneficial effects on this inflammatory condition.…”