Therapeutic Potential of Flavonoids in Pain and Inflammation: Mechanisms of Action, Pre-Clinical and Clinical Data, and Pharmaceutical Development

Abstract

Pathological pain can be initiated after inflammation and/or peripheral nerve injury. It is a consequence of the pathological functioning of the nervous system rather than only a symptom. In fact, pain is a significant social, health, and economic burden worldwide. Flavonoids are plant derivative compounds easily found in several fruits and vegetables and consumed in the daily food intake. Flavonoids vary in terms of classes, and while structurally unique, they share a basic structure formed by three rings, known as the flavan nucleus. Structural differences can be found in the pattern of substitution in one of these rings. The hydroxyl group (-OH) position in one of the rings determines the mechanisms of action of the flavonoids and reveals a complex multifunctional activity. Flavonoids have been widely used for their antioxidant, analgesic, and anti-inflammatory effects along with safe preclinical and clinical profiles. In this review, we discuss the preclinical and clinical evidence on the analgesic and anti-inflammatory proprieties of flavonoids. We also focus on how the development of formulations containing flavonoids, along with the understanding of their structure-activity relationship, can be harnessed to identify novel flavonoid-based therapies to treat pathological pain and inflammation.

Keywords: NF-kB; allodynia; analgesia; clinical trials; cytokines; flavonoid; hyperalgesia; hypersensitivity; inflammation; natural products.

Figure 1

The chemical structures of the flavonoid groups discussed in this review.

Figure 2

The number of manuscripts published on flavonoids, pain, and inflammation during the last 20 years at PubMed. The keywords search at PubMed was “flavonoids and pain and inflammation”, and only original research papers were considered.

Figure 3

The anti-inflammatory and analgesic effects of flavonoids. Intracellular targets of Rutin: NF-κB [39,40] and Nrf2 [40], Trans-chalcone: NF-κB [41] and STAT3 [41] and NLRP3 [42], Hesperidin: PI3K/ AKT [43] and NF-κB [44], Epigallocatechin-3-gallate: NF-κB [45], Apigerin: NF-κB [46], Diosmin: NF-κB [47], and Hesperidin methyl chalcone: NF-κB [48,49,50] and Nrf2 [49,50]. ROS and inflammatory stimuli that activate specific receptors trigger intracellular signaling that will result in pain and inflammation. The blue arrows indicate endogenous pathways that are stimulated by flavonoids resulting in the reduction of pain and inflammation. The red arrows represent endogenous pathways that are inhibited by flavonoids resulting in reduced pain and inflammation.

Figure 4

The anti-inflammatory and analgesic effects of Vitexin, Quercetin, and Naringenin. (A) Intracellular targets of Vitexin: MAPK [51], NF-κB [51] and Nrf2 [52], Quercetin: MAPK [53], NF-κB [53,54,55], AKT [56], Nrf2 [33,54], and NLRP3 [57] and Naringenin: NF-κB [58,59,60] and Nrf2 [59,61,62]. (B) Ion channels expressed by neurons that are targeted by Vitexin, Quercetin, and Naringenin to reduce pain. Vitexin: TRPV1 [38], Quercetin: TRPV1 [63], and Naringenin: TRPV1 [58], TRPA1 [58], TRPM3 [64], Nav 1.8 [65], and TRPM8 [64]. In panel (A), ROS and inflammatory stimuli that activate specific receptors trigger intracellular signaling that will result in pain and inflammation. The blue arrows indicate endogenous pathways that are stimulated by flavonoids, and the red arrows represent endogenous pathways that are inhibited by flavonoids resulting in reduced pain and inflammation.

Figure 5

The chemical structures of the flavonoids discussed in this review.