## 3 Polyphenols as Potential Agents in TMD
### Molecular Mechanisms of Polyphenols Targeting Inflammation  
Polyphenols have been proposed as potential agents to improve TMJ-related inflammatory states, concerning their ability to interfere with several pathways involved in the pathogenesis of this process [18; 19; 41]. Indeed, the protective role of dietary polyphenols in the management and progression of OA has been incrementally supported, which is a degenerative condition affecting the TMJ [19; 41]. Polyphenols could exert a potential protective effect against TMD, mainly through the modulation of chondrocytes inflammation and mitigation of cartilage destruction, resulting in the improvement of TMJ-related pain. Their modulatory activity is mediated by the interaction with important signaling pathways, including MAPKs and NF-\(\kappa\)B, as demonstrated in fibroblast-like synovivocytes (FLS) and the murine model of Collagen-Induced Arthritis (CIA) [19; 42]. Several studies have reported the reduction of pro-inflammatory cytokines, (TNF)-\(\alpha\), IL-6, and IL-1\(\beta\) and the modulation of COX-2 signaling pathway by polyphenols, such as p-coumaric acid, caffeic acid on different rat experimental models of inflammation, including monosodium urate crystal-induced inflammation in rats, formalin-induced pain in mice, and LPS-induced mechanical hyperalgesia in rats [20; 43; 44; 45; 46]. For example, the anti-inflammatory activity of polyphenol naringin has been demonstrated by an _in vitro_ study, showing a reduced production of prostaglandin E2, NO, IL-6, and TNF-\(\alpha\) in lipopolysaccharideaccharides (LPS)-induced RAW cells. This evidence is also supported by the improvement of tissue damage after treatment with naringin in a monosodium iodoacetate (MIA)-induced OA rat model [47].  
Beyond the anti-inflammatory activity of polyphenols, the ability to reduce symptoms related to TMJ pathological conditions is also associated with the anti- nociceptive effect. The reduction of ROS by polyphenols, including flavonoids, is strongly involved in this mechanism since they are responsible for spinal GABA release reduction and induction of neuropathic pain [48]. The anti-nociceptive action of quercetin has been shown by a study reporting the interaction with the L-arginine/NO pathway, serotonin, and GABAergic systems [49]. As described, quercetin (10-60 mg/kg) can reduce the nociception induced by glutamate in a mouse model of chemical and thermal nociception.  
Another interesting effect is the analgesic power of some compounds such as ferulic acid dimer (30 mg/kg) that in formalin-induced acute inflammatory pain mice acts through the interaction with adenosine receptors, a non-opioid mechanism, and novel pain target [50].  
Here, we will focus our attention on a selection of representative molecules, namely curcumin, resveratrol, epigallocatechin3-gallate (EGCG), and on polyphenol-based extracts, whose potential protective role against TMJ degenerative condition has been described by several scientific studies. For each of them, we will summarize their putative mechanism(s) of action from _in vitro_ and animal studies, and their potential applications in TMJ inflammation and TMD management will be discussed (Figure 2).