Comparative Effects of Curcumin and Tetrahydrocurcumin on Dextran Sulfate Sodium-induced Colitis and Inflammatory Signaling in Mice

Abstract

Background: Curcumin, a yellow ingredient of turmeric (Curcuma longa Linn, Zingiberaceae), has long been used in traditional folk medicine in the management of inflammatory disorders. Although curcumin has been reported to inhibit experimentally-induced colitis and carcinogenesis, the underlying molecular mechanisms remain largely unresolved.

Methods: Murine colitis was induced by dextran sulfate sodium (DSS) which mimics inflammatory bowel disease. Curcumin or tetrahydrocurcumin was given orally (0.1 or 0.25 mmol/kg body weight daily) for 7 days before and together with DSS administration (3% in tap water). Collected colon tissue was used for histologic and biochemical analyses.

Results: Administration of curcumin significantly attenuated the severity of DSS-induced colitis and the activation of NF-κB and STAT3 as well as expression of COX-2 and inducible nitric oxide synthase. In contrast to curcumin, its non-electrophilic analogue, tetrahydrocurcumin has much weaker inhibitory effects.

Conclusions: Intragastric administration of curcumin inhibited the experimentally induced murine colitis, which was associated with inhibition of pro-inflammatory signaling mediated by NF-κB and STAT3.

Keywords: Curcumin; Dextran sulfate sodium-induced colitis; NF-κB; STAT3; Tetrahydrocurcumin.

Figure 1

Effect of curcumin on (A) body weight loss and (B) colon length reduction in dextran sulfate sodium (DSS)-treated mice. Animal treatment and other experimental details are described in Materials and Methods section. *P < 0.05 and **P < 0.01.

Figure 2

Effect of curcumin on pathophysiologic conditions and histologic changes in dextran sulfate sodium (DSS)-induced murine colitis. (A) Disease activity index (DAI) as the sum of stool consistency and rectal bleeding was scored 0 to 3. Data are expressed as means ± SD (n = 5 per group). *P < 0.05 or **P < 0.01 vs. the DSS-treated group. The distal colon was stained by H&E. (B) Microscopic analysis of H&E-stained tissue sections shows that oral administration of curcumin (0.25 mmol/kg) significantly ameliorated damage of colonic mucosa caused by DSS. (a) Control; (b) DSS alone; (c) DSS + curcumin (0.1 mmmol/kg); (d) DSS + curcumin (0.25 mmol/kg).

Figure 3

Inhibitory effects of curcumin on dextran sulfate sodium (DSS)- induced DNA binding of NF-κB in mouse colon. The nuclear extracts was prepared from colon of each treatment group. Inhibitory effects of curcumin on DSS-induced NF-κB DNA binding were assessed by electrophoretic mobility shift assay as described in Materials and Methods. To ensure the specific NF-κB DNA binding, a competition assay was performed with 100-fold excess unlabeled oligonucleotides. Data are means ± SD (n = 5 per group). ***P < 0.001 vs. the DSS-treated group.

Figure 4

(A) The synthesis of tetrahydrocurcumin by catalytic hydrogenation of curcumin. (B) Effects of curcumin and tetrahydrocurcumin on dextran sulfate sodium (DSS)-induced colitis. Curcumin and tetrahydrocurcumin were treated to mice by gastric intubation at a dose of 0.25 mmol/kg each. Histology of H&E-stained mouse colon was visualized under a microscope. (a) Control; (b) DSS alone; (c) DSS + curcumin; (d) DSS + tetrahydrocurcumin.

Figure 5

Effects of curcumin (CUR) and tetrahydrocurcumin (THC) on activation of pro-inflammatory transcription factors and expression of their target proteins in the colon of dextran sulfate sodium (DSS)-treated mice. (A, B) The nuclear extracts from the colon of mice were prepared and subjected to electrophoretic mobility shift assay to assess DNA binding of NF-κB and STAT3 as described in Materials and Methods. (C) Colon tissues from mice treated with either CUR or THC and challenged with DSS were lysed. Lysates were subjected to immunoblot analysis to detect the expression of COX-2 and inducible nitric oxide synthase (iNOS).