Protective Effect of Resolvin D1, D2, and Their Methyl Esters on Oxidative Stress and Hyaluronidase—Induced Hyaluronic Acid Degradation

Hyaluronic acid (HA) injections are commonly employed in the management of osteoarthritis (OA), yet their therapeutic benefits are often limited by oxidative degradation and enzymatic breakdown within the joint. This study investigates whether Resolvin D1, Resolvin D2, and their methyl ester derivatives can enhance the efficacy of HA injections by acting as dual-function agents with both antioxidant and enzyme inhibitory properties. A comprehensive series of in vitro assays—including ORAC, FRAP, DPPH, ABTS, HRS, and SOD—were performed to evaluate antioxidant capacity, using Trolox, Ascorbic acid, β-Carotene, and Quercetin as reference standards. The potential to inhibit HA degradation was assessed through ROS-induced HA fragmentation and hyaluronidase inhibition assay, with epigallocatechin gallate (EGCG) serving as a positive control. The results indicate that Resolvin derivatives, particularly the methyl ester form of Resolvin D1, display mechanism-dependent antioxidant activity, showing pronounced effects in hydrogen atom transfer-based assays (e.g., ORAC and HRS), as well as in ABTS•+ and superoxide-related systems, along with protection against ROS and enzyme-induced HA degradation. These findings suggest that incorporating Resolvin derivatives may represent a promising strategy to improve HA-based viscosupplementation by enhancing stability and therapeutic persistence in osteoarthritic joints.