Molecular Insight into the Anti-Inflammatory Effects of the Curcumin Ester Prodrug Curcumin Diglutaric Acid In Vitro and In Vivo.

Rianthong Phumsuay,Pasarapa Towiwat,Chawanphat Muangnoi,Hasriadi Hasriadi,Opa Vajragupta,Peththa Wadu Dasuni Wasana,Pornchai Rojsitthisak

doi:10.3390/ijms21165700

Abstract

Curcumin diglutaric acid (CurDG), an ester prodrug of curcumin, has the potential to be developed as an anti-inflammatory agent due to its improved solubility and stability. In this study, the anti-inflammatory effects of CurDG were evaluated. The effects of CurDG on inflammatory mediators were evaluated in LPS-stimulated RAW 264.7 macrophage cells. CurDG reduced the increased levels of NO, IL-6, and TNF- α, as well as iNOS and COX-2 expression in cells to a greater extent than those of curcumin, along with the potent inhibition of MAPK (ERK1/2, JNK, and p38) activity. The anti-inflammatory effects were assessed in vivo by employing a carrageenan-induced mouse paw edema model. Oral administration of CurDG demonstrated significant anti-inflammatory effects in a dose-dependent manner in mice. The effects were significantly higher compared to those of curcumin at the corresponding doses (p < 0.05). Moreover, 25 mg/kg curcumin did not exert a significant anti-inflammatory effect for the overall time course as indicated by the area under the curve data, while the equimolar dose of CurDG produced significant anti-inflammatory effects comparable with 50, 100, and 200 mg/kg curcumin (p < 0.05). Similarly, CurDG significantly reduced the proinflammatory cytokine expression in paw edema tissues compared to curcumin (p < 0.05). These results provide the first experimental evidence for CurDG as a promising anti-inflammatory agent.

Highlights

Macrophage activation plays a primary role in host immune defense mechanisms, in the inflammatory response
The inflammation process is associated with the activation of nuclear factor kappa B (NF–κB) and phosphorylation of mitogen-activated protein kinases (MAPKs), namely p-38, c-Jun N-terminal kinases (JNKs), and extracellular-signal-regulated kinases (ERK1/2), resulting in the production and release of proinflammatory cytokines, including interleukin-1 beta (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-α); and increased levels of inflammatory mediators, namely nitric oxide (NO) and prostaglandin E2 (PGE2), which are generated by inducible nitric oxide synthase and cyclooxygenase-2 (COX-2), respectively [2]
Even though non-steroidal anti-inflammatory drugs (NSAIDs) are used in the management of acute inflammation, their undesirable effects have led to the search for new compounds from plants to be used in the prevention and treatment of inflammatory disorders with improved safety profiles

Summary

Introduction

Macrophage activation plays a primary role in host immune defense mechanisms, in the inflammatory response. Inflammation is a key response of the body that defends the body’s tissues against endogenous and exogenous stimuli, such as tissue damage, pathogens, and chemical irritants. Even though inflammation is considered as a physiological response to defend the host against both external and internal stimuli, it contributes to the pathophysiology of various chronic diseases, including rheumatoid arthritis, autoimmune disorders, atherosclerosis, and cancer [3] when these protective responses dysregulate. The downregulation of the inflammatory response would be a surrogate approach for the treatment and prevention of pathological complications associated with chronic inflammatory diseases. Even though non-steroidal anti-inflammatory drugs (NSAIDs) are used in the management of acute inflammation, their undesirable effects have led to the search for new compounds from plants to be used in the prevention and treatment of inflammatory disorders with improved safety profiles

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