Apixaban exhibits anti-arthritic effects by inhibiting activated factor X-mediated JAK2/STAT3 and MAPK phosphorylation p
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Inflammopharmacology
ORIGINAL ARTICLE
Apixaban exhibits anti‑arthritic effects by inhibiting activated factor X‑mediated JAK2/STAT3 and MAPK phosphorylation pathways Omnia Ahmed Mohamed Abd El‑Ghafar1 · Gouda Kamel Helal2 · Amira M. Abo‑Youssef3 Received: 5 August 2019 / Accepted: 10 February 2020 © Springer Nature Switzerland AG 2020
Abstract Activated factor X (FXa) is strongly linked to various inflammatory events. This study aimed to investigate the effect of FXa on janus kinase2/signal transducers and activators of transcription3 (JAK2/STAT3) and mitogen-activated protein kinase (MAPK) phosphorylation in relation to rheumatoid arthritis (RA). It also extends its scope to explore the possible antiarthritic effects of apixaban, a selective FXa inhibitor. Rats were allocated into normal control; complete Freund’s adjuvant (CFA, 0.4 ml/4 days/12 days); FXa (120 µg/kg/day/3 days) and CFA + FXa groups as well as three treated groups including CFA + apixaban; FXa + apixaban and CFA + FXa + apixaban. Apixaban was administered at a dose of 10 mg/kg/12 h for15 days. By the end of the experimental period, tissue samples were collected for the assessment of phosphorylated (p)-JAK2, STAT3, MAPK, matrixmetalloprotein-1 (MMP-1) and protease-activated receptor 2. Furthermore, Serum interleukin-6 (IL-6), platelet-derived growth factor (PDGF), anti-citrullinated protein antibody (ACPA), 8-hydroxy-2′-deoxyguanosine (8-OHdG), plasma level of FXa and prothrombin time were evaluated. In support, histopathological and macroscopical examinations were performed. FXa activated JAK2, STAT3 and MAPK phosphorylation through activation of PAR 2, PDGF and IL-6 and concomitantly led to a significant elevation in ACPA, MMP-1 and 8-OHdG. Apixaban markedly amended FXa-induced changes. Conclusively, the current study revealed that FXa may have a drastic role in RA progression and pathogenesis at least through stimulation of JAK2/STAT3 and MAPK phosphorylation. Furthermore, apixaban exerted robust arthro-protective effects. These beneficial outcomes could be attributed to its ability to impede JAK2/STAT3 and MAPK activation, as well as to its antioxidant property. Keywords Rheumatoid arthritis · Fxa · JAK2/STAT3 pathway · MAPK pathway
Introduction
* Omnia Ahmed Mohamed Abd El‑Ghafar [email protected] * Amira M. Abo‑Youssef [email protected] Gouda Kamel Helal [email protected] 1
Pharmacology and Toxicology Department, Faculty of Pharmacy, Nahda University, Kornish Al Nil, Bayad Al Arab, Beni Suef, Egypt
2
Pharmacology and Toxicology Department, Faculty of Pharmacy, Heliopolis University for Sustainable Development, 3 Cairo‑Belbeis Desert Rd, Second Al Salam, Cairo, Egypt
3
Pharmacology and Toxicology Department, Faculty of Pharmacy, Beni-Suef University, Beni Suef, Egypt
Rheumatoid arthritis (RA) is the most prevailing systemic inflammatory auto-immune disorder correlated with synovial inflammation, autoantibody production and anti-citrullinated protein antibody (ACPA) generation (Krishnamurthy et al.
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