## 7 Discussion  
OA is a very common degenerative disease. This disease is characterized by structural loss and functional impairment of the joints, leading to disability [24; 25; 26]. Whereas there is no cure for OA to date, most of the treatments available are intended to control pain and uphold joint function. Usually, the treatment of OA begins with safer and less invasive therapies, such as physical activity. This is because the benefits of exercise can lead to the prevention of obesity and maintenance of normal joint health [27; 28]. If OA pain cannot be controlled by physical therapy, different pharmacological treatments are available. Paracetamol is usually the first line drug therapy in OA [29; 30]. If paracetamol is not successful, the next level of pharmacological treatment varies according to the patient, but usually involves the use of non-steroidal topical or oral anti-inflammatory drugs (NSAIDs); topical capsaicin, and injections of intra-articular corticosteroids and opioids [31; 32]. However, these drugs expose patients to the risk of liver and kidney damage [30]. In addition, these medicines often offer only partial relief [33; 34] and do not help the body rebuild the damaged joint cartilage [35]. Numerous studies have shown a role of ROS in the pathogenesis of chronic inflammatory arthropathy, such as OA [36]. Therefore, researchers are considering a multifactorial approach to managing OA. HA is secreted by chondrocytes and used for cartilage synthesis. According to the research, HA is helpful in the control of OA as it interferes with pain mediators and crucial enzymes (such as metalloproteinase) that are responsible for the digestion and destruction of healthy cartilage tissue [37; 38]. HA is generally administered intraarticularly, and also orally [39; 40; 41]. New products are frequently being developed that modify the composition of the molecule and associate it with other drugs to maximize the effect [37; 42]. CARN is a dipeptide consisting of \(\beta\)-alanine and L-histidine. The anti-inflammatory potential of CARN has been studied in autoimmune diseases [43]. Furthermore, the ability of CARN as an antioxidant, and the anti-glycating and toxic metal-ion chelating properties are well documented [44]. In previous studies the capacity of CARN in the regression of the senescence of cultured human fibroblasts and in delaying aging has been highlighted; however, the mechanisms remain uncertain [45]. Furthermore, it has been shown that CARN reduces the oxidative damage on chondrocytes and prevents cartilage degradation in the \"arthritic\" joints [43]. However, the anti-inflammatory potential of CARN in OA is still poorly studied. In a recent report, the potential protective effect of an oral CARN supplement was assessed to improve type 2 diabetes-induced OA [46]. Based on the studies performed on HA and CARN, the aim of this study was to evaluate the synergistic effect of a new formulation called FidHycarn, consisting of the covalent conjugation of these two substances, in an in vivo MIA model. In this regard, we have shown that the oral administration of the conjugated FidHycarn was able to improve behavioral deficits and to reduce macroscopic, histological, and radiographic alterations in a more significant way compared to the administration of single compounds or carnosine+HA association. Oxidative stress shows a potential role on the pathogenesis of OA. In subjects suffering from OA there is a reduction in antioxidants [47]. Proinflammatory cytokines (IL-1\(\beta\), IL-6, and TNF-\(\alpha\)), chemokines (MIP-I\(\alpha\) and MIP-2), and NO also play an important function in the pathogenesis of joint damage [48; 49; 50]. In this regard, in this study, it was found that in rats with OA, treated with carnosine or HA or carnosine+HA, the levels of pro-inflammatory cytokines and chemokines were not significantly reduced. In contrast, in FidHycarn-treated rats, a significant diminution of these proteins was observed.