Preclinical efficacy of a gastro-sparing novel thiazolidin-4-one in alleviating secondary lesions of polyarthritis: A multi-parametric approach Jayesh Mudgal a , Vasantharaju S. Gowdra b , Piya P. Mudgal c , Pawan G. Nayak a , Nitesh Kumar a , Zenab Attari d , C. Mallikarjuna Rao a , Gopalan K. Nampurath a, ⁎ a Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal University, Manipal 576 104, Karnataka, India b Department of Pharmaceutical Quality Assurance, Manipal College of Pharmaceutical Sciences, Manipal University, Manipal 576 104, Karnataka, India c Department of Virus Research (Manipal Centre for Virus Research), Manipal University, Manipal 576 104, Karnataka, India d Department of Pharmaceutics, Manipal College of Pharmaceutical Sciences, Manipal University, Manipal 576 104, Karnataka, India abstract article info Article history: Received 18 February 2016 Received in revised form 11 May 2016 Accepted 4 June 2016 Available online 06 June 2016 The promising role of thiazolidin-4-ones (TZOs) against inflammatory conditions has been reported. From our lab, one of the TZO derivatives, compound 4C, exerted anti-inflammatory potential via inhibition of locally re- leased cytokines and prostaglandin. In continuance, a detailed study was undertaken for the preclinical profiling of this promising TZO derivative against polyarthritis in rats, along with assessment of risk associated with the treatment. Male Sprague-Dawley rats were used for the adjuvant-induced arthritis (AIA) model. Based on the de- velopment of secondary lesion, the animals were randomized into different treatment groups. To establish the efficacy of the test compound, parameters such as inflammation, pain, disease progression, cytokines and pros- taglandin (PG)-E 2 levels and complete blood cell profile were recorded along with radiological and histological examinations of joints. The study also focused on evaluating the side effect of test compound on gastric, liver, renal, blood and cardiovascular components. Compound 4C exerted promising therapeutic effect against second- ary lesions in polyarthritis in rats. It limited the progression of chronic inflammation and associated pain in rats. Modulation of cytokine signalling and arachidonate metabolism by 4C was evident from inhibition of interleukin (IL)-6, tumor necrosis factor (TNF)-α and PGE 2 generation in AIA rats. Comparatively, compound 4C was safer than diclofenac to cause gastric, liver, renal, blood and cardiovascular toxicities. These finding supports the effi- cacy and safety profile of 4C, a TZO derivative in limiting the progression of arthritis when administered orally. © 2016 Elsevier B.V. All rights reserved. Keywords: Thiazolidin-4-one Cytokines Prostaglandin Analgesic Anti-inflammatory Gastro-sparing 1. Introduction Rheumatoid arthritis represents a chronic inflammatory condition of autoimmune origin. Early diagnosis of arthritis and early management are the best tools for improving the patient's quality of life. Treatment strategy for an arthritic patient is adopted based upon the stage of ar- thritis. Management of arthritis is focused primarily on preventing the disease progression to the other digits/joints. According to American College of Rheumatology Subcommittee on Rheumatoid Arthritis Guidelines (American College of Rheumatology Subcommittee on Rheumatoid Arthritis, G., 2002), disease modifying antirheumatic drugs (DMARDs) such as hydroxychloroquine and sulfasalazine are the first line therapy for mild arthritis with no erosions visible on radio- graphs. Moderate or severe arthritis involves the management of arthri- tis with immunosuppressants like methotrexate, leflunomide and azathioprine with or without biologics. Several reports are available on the involvement of cytokine signal- ling in the progression of arthritis. Among the anti-cytokines regime, anti-TNF-alpha and anti-IL-6 have been developed and are being used for the severe form of arthritis along with conventional DMARDs (Choy, 2012; Song and Yoshizaki, 2015). Recent report also claims the promising effect of combined inhibition of TNF-alpha and IL-17 cyto- kines as a promising strategy towards achieving the therapeutic goal for the treatment of arthritis (Fischer et al., 2015). Inhibition of IL-17 alone (van den Berg and Miossec, 2009) or in combination with TNF- alpha also has emerged as a newer approach for the treatment of arthritis (Fischer et al., 2015). The approach of combined inhibition of cytokines has shown promising effect over single cytokine inhibition, as the latter possesses meaningful response only in 50% of arthritic European Journal of Pharmaceutical Sciences 91 (2016) 74–83 Abbreviations: 4C, 2-(4-chlorophenoxy)-N-(5-methyl-4-oxo-2-(pyridin-2-yl) thiazolidin-3-yl) acetamide; AIA, Adjuvant-induced polyarthritis; DF, Diclofenac; NC, Normal control; TZO, Thiazolidin-4-one. ⁎ Corresponding author at: Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal University, Manipal 576104, Karnataka, India. E-mail address: ng.kutty@manipal.edu (G.K. Nampurath). http://dx.doi.org/10.1016/j.ejps.2016.06.002 0928-0987/© 2016 Elsevier B.V. All rights reserved. Contents lists available at ScienceDirect European Journal of Pharmaceutical Sciences journal homepage: www.elsevier.com/locate/ejps