Ginsenoside Rd attenuates the inflammatory response via modulating p38 and JNK signaling pathways in rats with TNBS-induced relapsing colitis

https://doi.org/10.1016/j.intimp.2011.12.014Get rights and content

Abstract

In this study, we investigated the effects and the protective mechanism of ginsenoside Rd (GRd) which has been identified as one of the effective compounds from ginseng on relapsing colitis model induced by 2,4,6-trinitrobenzenesulfonic acid (TNBS) in rats. After inducing relapsing colitis in experimental rats on two occasions by intracolonic injection of TNBS, GRd (10, 20 and 40 mg/kg) was administered to experimental colitis rats for 7 days. The inflammatory degree was assessed by macroscopic score, histology and myeloperoxidase (MPO) activity. The levels of proinflammatory cytokines, such as TNF-α, IL-1β, and IL-6 were determined by ELISA. Mitogen-activated protein kinase (MAPK) phosphorylation was analyzed by western blotting method. The results showed that GRd markedly attenuates the inflammatory response to TNBS-induced relapsing colitis, as evidenced by improved signs, increased body weight, decreased colonic weight/length ratio, reduced colonic macroscopic and microscopic damage scores, inhibited the activity of MPO, lowered proinflammatory cytokine levels and suppressed phosphorylation of p38 and JNK. The possible mechanism of protection on experimental colitis after GRd administration was that it could reduce the accumulation of leukocytes and down-regulate multiple proinflammatory cytokines through modulation of JNK and p38 activation.

Highlights

► GRd possesses markedly protective effects on experimental colitis. ► GRd inhibits TNBS-induced proinflammatory cytokine release. ► P38 and JNK, but not ERK1/2, play important role in TNBS-induced relapsing colitis. ► GRd's protective effects are based on anti-inflammatory and pharmacokinetic properties of it.

Introduction

Inflammatory bowel disease (IBD) is characterized as a chronic idiopathic inflammation of the intestine. It is an umbrella term for different diseases of which ulcerative colitis and Crohn's disease (CD) are the two most common entities [1]. At present, medical treatment of IBD relies mainly on glucocorticoids, 5-aminosalicylic acid, and immunosuppressive agents. The limitations in both efficacy and safety encountered continue to drive the search for better therapeutic options [2]. IBD presents a challenging target for drug delivery, particularly by the oral route, as contrary to most therapeutic regimens, minimal systemic absorption and maximal intestinal wall drug levels are desired [3].

Ginseng is a perennial herb of the Araliaceae family, species in the genus Panax, and a highly valued medicinal plant in the Far East that has gained popularity in the West during the past decade [4], [5]. Ginseng is reported to have a wide range of therapeutic and pharmacological uses [6]. Researchers are now focused on using purified individual ginsenoside to reveal the mechanism of functions of ginseng instead of using whole ginseng root [7], [8]. Ginsenosides appear to be responsible for most of the activities of ginseng including vasorelaxation, antioxidation, anti-inflammation and anticancer. Ginsenoside Rd (GRd) has been identified as one of the effective compounds responsible for the pharmaceutical actions of ginseng [9]. GRd is a putative antioxidant in that it targets many of the key players involved in inflammation [10], [11], [12]. Wu et al. [10] suggested that GRd exerted its anti-inflammatory effects by inhibiting proinflammatory cytokines (such as tumor necrosis factor-α (TNF-α)) production and interfering with mitogen-activated protein kinase (MAPK) signaling pathways. Tamura et al. [13] reported that GRd may prevent and rescue rat intestinal epithelial cells from irradiation-induced apoptosis. Since IBD is a chronic inflammatory disease, we supposed that GRd can be used to treat colitis.

Generally, ginsenosides are very poorly absorbed following oral administration in vivo [14]. Wang et al. [15] reported the absolute bioavailability of GRd in dogs was 0.26%. Li et al. [16] reported the absolute bioavailability of GRd in rats was 0.34%. Our laboratory's results revealed that most of the GRd was found in the colon after oral administration (to be published). One of the reasons of the poor bioavailability of GRd is that it may be metabolized by colonic microflora [17]. This pharmacokinetic characteristic suggests that GRd affects the colonic mucosa directly, so that it has a natural colon-targeting feature that may be of therapeutic interest in colitis.

Based upon anti-inflammatory and pharmacokinetic properties of GRd, we examined the protective role and mechanism of GRd against 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced relapsing colitis in rats.

Section snippets

Drugs and reagents

GRd was obtained from Guangdong Taihe Biological Pharmaceutical Co. Ltd. (Gongdong, China). Sulfasalazine (SASP) was supplied by Sine Pharmaceutical Co. Ltd. (Shanghai, China). TNBS was obtained from Sigma Chemical Co. Ltd. (St. Louis, MO, USA). Myeloperoxidase (MPO) kits were purchased from Nanjing Jiancheng Bioengineering Institute (Nanjing, China). Rat TNF-α, interleukin-1β (IL-1β), and IL-6 platinum ELISA kits were purchased from Bender (Bender MedSystems, CA, USA). RIPA Lysis Buffer was

General observation

At the second rectal administration of TNBS, the rats from the TNBS group quickly developed signs, including bloody diarrhea, poor coat quality, body weight loss, and reduced mobility. However, all the above-described signs in the SASP group and GRd group were minor compared with those in the TNBS group.

Body weight change

There was a non-significant difference in body weight between the groups before the experiment. At the end of the experiment (before the rats were killed), the body weight of the TNBS group was

Discussion

The present study revealed that GRd markedly attenuates the inflammatory response to TNBS-induced relapsing colitis. This is evidenced by improved signs, increased body weight, decreased colonic weight/length ratio, reduced colonic macroscopic and microscopic damage scores, inhibited activity of MPO, lowered proinflammatory cytokine levels and suppressed phosphorylation of p38 and JNK.

The experimental model of colitis induced by intrarectal administration of TNBS provides clinical and

Acknowledgments

This study was supported by grants from the Key National S&T Program “Major New Drug Development” of the Ministry of Science and Technology (No. 2009ZX09503-017) and the Natural Science Foundation of Gansu Province of China (No. 1010RJZA115).

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