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

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.

Protective Effects of a Lutein Ester Prodrug, Lutein Diglutaric Acid, against H2O2-Induced Oxidative Stress in Human Retinal Pigment Epithelial Cells

“…Several studies showed that the prodrug and formulation development of drugs and bioactive compounds could improve bioavailability and biological activities [ 39 , 40 , 41 , 58 ]. A previous study showed that the phospholipid complex of quercetin could improve the solubility of quercetin and enhance the protective effect against oxidative-induced damages in ARPE-19 cells compared to quercetin [ 50 ].…”

“…The prodrug approach has been shown to enhance pharmacological properties by improving physico-chemical and biopharmaceutical properties such as aqueous solubility, stability, bioavailability and biological activities [ 36 , 37 , 38 , 39 , 40 , 41 , 42 ]. We have previously demonstrated that curcumin digluatric acid, an ester prodrug of curcumin conjugated with diglutaric acid, improved the biological activities of curcumin both in vitro and in vivo [ 41 , 42 ], suggesting that glutaric acid could serve as a promoiety of bioactive molecules. The conjugation of Lut with diglutaric acid via an ester bond can possibly increase the pharmacological and biological activities of Lut.…”

Targeting phytoprotection in the COVID-19-induced lung damage and associated systemic effects—the evidence-based 3PM proposition to mitigate individual risks

“…Curcumin exerts various pharmacological activities, including antioxidant, anticancer, anti-inflammatory, and anti-infective. Curcumin affects various signaling molecules associated with the inflammatory processes, such as TNF-α, IL-1β, NF-κB, COX-2, and iNOS [165,166]. Curcumin was observed to regulate the differentiation of naïve CD4+T cells and activate IL-10 immune modulation against acute lung injury in mice and thus alleviated lung injury and suppressed uncontrolled inflammation [167].…”

Anti-Inflammatory Activity of Cnidoscolus aconitifolius (Mill.) Ethyl Acetate Extract on Croton Oil-Induced Mouse Ear Edema

“…Inflammation, considered as one of the principal responses of the immune system, involves redness, swelling, pain, heat, and dysfunction [10]. Non-steroidal anti-inflammatory drugs are used to treat inflammation.…”