Combinatory Effects of Bone Marrow-Derived Mesenchymal Stem Cells and Indomethacin on Adjuvant-Induced Arthritis in Wistar Rats: Roles of IL-1 β, IL-4, Nrf-2, and Oxidative Stress

Eman A Ahmed; Osama M Ahmed; Hanaa I Fahim; Emad A Mahdi; Tarek M Ali; Basem H Elesawy; Mohamed B Ashour

doi:10.1155/2021/8899143

Combinatory Effects of Bone Marrow-Derived Mesenchymal Stem Cells and Indomethacin on Adjuvant-Induced Arthritis in Wistar Rats: Roles of IL-1 β, IL-4, Nrf-2, and Oxidative Stress

Evid Based Complement Alternat Med. 2021 Jan 5:2021:8899143. doi: 10.1155/2021/8899143. eCollection 2021.

Authors

Eman A Ahmed¹, Osama M Ahmed¹, Hanaa I Fahim¹, Emad A Mahdi², Tarek M Ali^{3

4}, Basem H Elesawy^{5

6}, Mohamed B Ashour¹

Affiliations

¹ Physiology Division, Zoology Department, Faculty of Science, Beni-Suef University, P.O. Box 62521, Beni-Suef, Egypt.
² Pathology Department, Faculty of Veterinary Medicine, Beni-Suef University, Beni-Suef, Egypt.
³ Department of Physiology, College of Medicine, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia.
⁴ Department of Physiology, Faculty of Medicine, Beni-Suef University, Beni-Suef, Egypt.
⁵ Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia.
⁶ Department of Pathology, Faculty of Medicine, Mansoura University, Mansoura, Egypt.

Abstract

Rheumatoid arthritis (RA) is a disorder triggered by autoimmune reactions and related with chronic inflammation and severe disability. Bone Marrow-derived Mesenchymal Stem Cells (BM-MSCs) have shown a hopeful immunomodulatory effect towards repairing cartilage and restoring joint function. Additionally, indomethacin (IMC), a nonsteroidal compound, has been considered as a potent therapeutic agent that exhibits significant antipyretic properties and analgesic effects. The target of the current research is to assess the antiarthritic efficacy of BM-MSCs (10⁶ cells/rat at 1, 6, 12 and 18 days) and IMC (2 mg/kg body weight/day for 3 weeks) either alone or concurrently administered against complete Freund's adjuvant-induced arthritic rats. Changes in paw volume, body weight, gross lesions, and antioxidant defense system, as well as oxidative stress, were assessed. The Th1 cytokine (IL-1β) serum level and Th2 cytokine (IL-4) and Nrf-2 ankle joint expression were detected. In comparison to normal rats, it was found that the CFA-induced arthritic rats exhibited significant leukocytosis and increase in paw volume, LPO level, RF, and IL-1β serum levels. In parallel, arthritic rats that received BM-MSCs and/or IMC efficiently exhibited decrease in paw edema, leukocytosis, and enhancement in the antioxidant enzymatic levels of SOD, GPx, GST, and GSH in serum besides upregulation of Nrf-2 and anti-inflammatory IL-4 expression levels in the ankle articular joint. Likewise, these analyses were more evidenced by the histopathological sections and histological score. The data also revealed that the combined administration of BM-MSC and IMC was more potent in suppressing inflammation and enhancing the anti-inflammatory pathway than each agent alone. Thus, it can be concluded that the combined therapy with BM-MSC and IMC may be used as a promising therapeutic choice after assessing their efficacy and safety in human beings with RA, and the antiarthritic effects may be mediated via modulatory effects on Th1/Th2 cytokines, ozidative stress, and Nrf-2.