ORIGINAL ARTICLE Novel Anti-arthritic Mechanisms of Polydatin in Complete Freund’ s Adjuvant-Induced Arthritis in Rats: Involvement of IL-6, STAT-3, IL-17, and NF-кB Kamel M. Kamel , 1,5 Amany M. Gad, 1 Suzan M. Mansour, 2,3 Marwa M. Safar, 2,4 and Hala M. Fawzy 1 Abstract— Articular manifestations are the main hall mark for rheumatoid arthritis; inflam- mation and oxidative stress are involved in its pathogenesis. This study was designed to figure out the possible therapeutic potential of polydatin on experimentally induced arthritis in rats. Polydatin (POLY) was administered (200 mg/kg, p. o.) for 21 days to complete Freund’ s adjuvant (CFA; 0.1 ml, s.c.)-induced arthritic rats. Meanwhile, methotrexate (MTX; 0.75 mg/kg, i.p.) was given as a reference standard disease-modifying anti-rheumatic drug (DMARD). Both POLY and MTX significantly attenuated articular damage associated with CFA-induced arthritis. This was mani- fested by reducing levels of tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), interleukin- 17 (IL-17), and matrix metalloproteinase-3 (MMP-3), paralleled with marked decrease in hind paw and ankle diameters. Moreover, POLY and MTX downregulated gene expressions of receptor activator of nuclear factor kappa-B ligand (RANKL) as well as signal transducer and activator of transcription-3 (STAT3) besides hampering immunohistochemical staining of vascu- lar endothelial growth factor (VEGF) and nuclear factor kappa-B (NF-κB). Furthermore, sub- stantial decline in myeloperoxidase (MPO) activity and malondialdehyde (MDA) level associated with significant rise in reduced glutathione content (GSH) was observed. These findings provide an innovative therapeutic approach of POLY as a natural anti-arthritic drug through modulating IL-6/STAT-3/IL-17/NF-кB cascade. KEY WORDS: polydatin; methotrexate; cytokines; synovitis; pannus. INTRODUCTION Rheumatoid arthritis (RA) is one of the most common autoimmune diseases that is characterized by chronic in- flammatory manifestations, systemic complications, car- diovascular risk, and even increased mortality [1–3]. The mechanisms by which RA is initiated and aggravated are not yet fully understood [4]. However, the involvement of different immune cell populations, numerous pro- inflammatory cytokines, and inflammatory mediators is affirmed [5]. 1 Pharmacology Department, National Organization for Drug Control and Research, 6 Abou Hazem St., Pyramids Ave., Giza, Egypt 2 Pharmacology & Toxicology Department, Faculty of Pharmacy, Cairo University, Kasr El-Aini St., Cairo, 11562, Egypt 3 Pharmacology, Toxicology & Biochemistry Department, Faculty of Pharmaceutical Sciences and Pharmaceutical Industries, Future Univer- sity in Egypt, End of 90th St., Fifth Settlement, New Cairo, Egypt 4 Pharmacology & Biochemistry Department, Faculty of Pharmacy, The British University in Egypt, Suez Desert Road, El Sherouk City, Cairo 11837, Egypt 5 To whom correspondence should be addressed at Pharmacology Depart- ment, National Organization for Drug Control and Research, 6 Abou Hazem St., Pyramids Ave., Giza, Egypt. E-mail: doctorkamelmohamed@gmail.com 0360-3997/18/0000-0001/0 # 2018 Springer Science+Business Media, LLC, part of Springer Nature Inflammation ( # 2018) DOI: 10.1007/s10753-018-0841-4