Inflammation occurs in response to a wide variety of stimuli including microbial, physical (e.g., trauma) or chemical injury and it is essentially a beneficial reaction, since it represents the first response of the organism to “injury.” However, inflammation can turn into a chronic state that leads to the destruction of the involved body structures due to the generation of powerful biochemical mediators. Comfrey also contains pyrrolizidine alkaloids such as 7-acetylintermedine, 7-acetyllycopsamine, intermedine, lycopsamine, and symphytine ( Brauchli et al., 1982) that can cause liver toxicity ( Ridker et al., 1985 Stickel and Seitz, 2000 Trifan et al., 2018), and, thereby, some medicinal products use pyrrolizidine alkaloid-depleted extracts as active ingredients. The constituents of comfrey root include allantoin, mucilage polysaccharides, phenolic compounds including rosmarinic acid, chlorogenic acid, caffeic acid and derivatives, glycopeptides, and triterpene saponins ( Staiger, 2012 Sowa et al., 2018). To date, the therapeutic value of preparations from comfrey root is widely accepted, and they have been marketed in more than 10 countries.
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In addition, the European Scientific Cooperative on Phytotherapy provides information about the use of comfrey for tendinitis syndrome, knee joint injuries, non-active gonarthrosis, insect bites, mastitis, fractures, and skin inflammation ( ESCOP, 2009). for the external use in bruises, strains, and sprains and led to the acknowledgment of its anti-inflammatory action ( Kommission, 1990). An assessment from the German Commission E resulted in the positive evaluationof comfrey root derived from S. Specified therein, its application is shown to significantly reduce pain and swelling, contribute to tissue regeneration, and result in a more rapid functional improvement. Comfrey was proven effective for the treatment of, e.g., acute upper and lower back pain, gonarthrosis, or for patients with blunt injuries ( Koll et al., 2004 Predel et al., 2005 Grube et al., 2007 Giannetti et al., 2010). Today, the efficacy and safety of comfrey root extract ointment has been substantiated by several randomized clinical trials and non-interventional studies. Several cellular mechanisms have been proposed in order to explain their mode of action, including the targeting of different intracellular signaling pathways triggered by NF-κB, AP-1, PPAR, Nrf2, and MAPKs ( Chen et al., 2017 Tasneem et al., 2019). Phenolic compounds have been reported to exert anti-inflammatory effects both in vitro and in vivo ( Chen et al., 2018). Native in Europe, it has been used for centuries for the treatment of a variety of painful muscle and joint complaints ( Staiger, 2012 Frost et al., 2013). Symphytum officinale (Boraginaceae), well known as comfrey, represents a plant with an impressive record of medicinal use.
These results provide a first mechanistic insight into the mode of action of a century-old popular herbal medicine. Furthermore, our biochemical studies provide evidence that comfrey inhibits NF-κB signaling at two stages: it dampens not only the activation of IKK1/2 and the subsequent IκBα degradation, but also interferes with NF-κB p65 nucleo-cytoplasmatic shuttling and transactivation. Both preparations inhibit the activation of NF-κB, a transcription factor of central importance for the expression of these and other pro-inflammatory genes. The extract, and especially its mucilage-depleted fraction, impair the interleukin-1 (IL-1) induced expression of pro-inflammatory markers including E-selectin, VCAM1, ICAM1, and COX-2. Here, we show that a hydroalcoholic extract of comfrey root impairs the development of a pro-inflammatory scenario in primary human endothelial cells in a dose-dependent manner. However, the molecular basis of its action remained elusive. Today, its topical use is based on its analgesic and anti-inflammatory effects, which have been substantiated by modern clinical trials. Symphytum officinale, commonly known as comfrey, constitutes a traditional medicinal plant with a long-standing therapeutic history, and preparations thereof have been widely used for the treatment of painful muscle and joint complaints, wound and bone healing, and inflammation. 3Dipartimento di Farmacia, Università degli Studi di Salerno, Salerno, Italy.2R&D, Procter & Gamble Health, Darmstadt, Germany.
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