Mechanism and Effect of Esculetin in an Experimental Animal Model of Inflammatory Bowel Disease

Abstract

Esculetin is a coumarin derivative with high antioxidant activity. In a rat experimental model of inflammatory bowel disease induced by trinitrobenzenesulfonic acid, esculetin at the dose of 5mg/Kg displayed intestinal anti-inflammatory activity; however, its mechanism of action needs to be elucidated. Our objective was to evaluate the effects of esculetin on the intestinal inflammatory process and to clarify the mechanism of action of this compound. We also compared its effects with prednisolone and sulphasalazine. Our results demonstrate that treatment with esculetin prevented an increase in malondialdehyde content, counteracted the depletion of glutathione content, reduced epithelial cell apoptosis, reduced the secretion of pro-inflammatory cytokines, such as IL-lP, IL-2 and IFN-y, in vitro, and reduced the colonic levels of TNF-a and IL-IP in vivo. Additionally, esculetin treatment inhibited MPO and AP activities. These results demonstrated that esculetin produced a more effective intestinal anti-inflammatory effect than sulphasalazine because it was used at a lO-fold lower dose, and it produced effects similar to those created by prednisolone. We suggest that esculetin exerts its activity by inhibiting pro-inflammatory cytokine secretion and increasing the defences against reactive oxygen species. This leads to less migration and/or activation of inflammatory cells, resulting in the improvement of lesions and functions in the intestinal epithelium. This study confirms the intestinal anti-inflammatory activity of esculetin and demonstrates that this compound has both antioxidative and immunomodulatory properties. Therefore, esculetin may be an interesting new anti-inflammatory drug for the treatment of inflammatory bowel disease.Inflammatory bowel disease (IBD) is a chronic inflammatory condition of the gastrointestinal tract. IBD is divided into two major categories, ulcerative colitis (UC) and Crohn's disease (CD). The cause of IBD is not known; however, the actual development of disease reflects the contributions of host genetics, an environmental trigger and the consequent immune response (l). Current drugs for IBD

Esculetin: A review of its pharmacology and pharmacokinetics

“…As pieces of evidence showed, via inducing the expression of antioxidant enzyme HO-1, esculetin significantly inhibited the release of proinflammatory cytokines and mediators, including NO, TNF-α, and MCP-1 (Kim et al, 2014). Moreover, through increasing the defense against ROS, the suppression of the activation and migration of inflammatory cells was found to be helpful for esculetin (Witaicenis et al, 2013). In general, esculetin showed significant potential to be a future therapeutic candidate for the treatment of inflammatory diseases.…”

“…The downregulation of the HIF-prolyl hydroxylase (HPH) expression by esculetin (200 μM), leading to the activation of the HIF-1-VEGF pathway that triggers beneficial effects to colitis was suggested by Yum et al (2015). In rats with colitis, it was suggested by Witaicenis et al that esculetin with a dosage of 5 mg/kg not only increases the defense against ROS but also inhibits the secretion of proinflammatory cytokines, including tumor necrosis factor (TNF)-α, interleukin (IL)-lβ, IL-2, and interferon (IFN)-γ, leading to the lower activation and less migration of inflammatory cells (Witaicenis et al, 2013). In mice with fibromyalgia induced by reserpine, esculetin (10 mg/kg) was demonstrated to relieve behavioral and biochemical deficits through the inhibition of the release of proinflammatory cytokines (TNF-α and IL-lβ) as well as the monoamine oxidase-A (MAO-A)mediated depletion of serotonin (Singh et al, 2020).…”

Dietary Coumarins

“…Rzodkiewicz et al (2016) showed that 8 could reduce leukotriene B4 level in plasma of rats with adjuvant-induced arthritis, indicating its potential as a drug candidate for the treatment of rheumatoid arthritis. In a rat experimental model of inflammatory bowel disease induced by trinitrobenzenesulfonic acid, coumarin 8 at the dose of 5 mg/Kg exhibited intestinal anti-inflammatory activity (Witaicenis et al 2014).…”

Mechanistic insights into the biochemical and pharmacological profile of esculetin

“…[53]. Esculetin has been shown to obstruct the inflammatory cascade by downregulating the expression of IL-1β, IL-2, IFN-γ, and TNF-α in inflammatory bowel disease [54] and fibromyalgia [55]. Furthermore, esculetin exhibits anti-allergic and anti-inflammatory activity by downregulating the expression of IL-6 and IL-8 in the nasal epithelial cells under in vitro conditions [56].…”