Ginsenoside Rd attenuates the inflammatory response via modulating p38 and JNK signaling pathways in rats with TNBS-induced relapsing colitis
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).
References (47)
- et al.
MAP kinases in inflammatory bowel disease
Clin Chim Acta
(2011) - et al.
Ginseng pharmacology: multiple constituents and multiple actions
Biochem Pharmacol
(1999) - et al.
Differential effects of ginsenosides on NO and TNF-alpha production by LPS-activated N9 microglia
Int Immunopharmacol
(2007) - et al.
Ginsenoside Rd prevents and rescues rat intestinal epithelial cells from irradiation-induced apoptosis
Food Chem Toxicol
(2008) - et al.
Determination of 25-OH-PPD in rat plasma by high-performance liquid chromatography-mass spectrometry and its application in rat pharmacokinetic studies
J Chromatogr B Analyt Technol Biomed Life Sci
(2007) - et al.
Determination of GRd in dog plasma by liquid chromatography-mass spectrometry after solid-phase extraction and its application in dog pharmacokinetics studies
J Chromatogr B Analyt Technol Biomed Life Sci
(2007) - et al.
Quantitative assay for acute intestinal inflammation based on myeloperoxidase activity. Assessment of inflammation in rat and hamster models
Gastroenterology
(1984) - et al.
Methotrexate is effective in reactivated colitis and reduces inflammatory alterations in mesenteric adipose tissue during intestinal inflammation
Pharmacol Res
(2009) - et al.
Measurement of cutaneous inflammation: estimation of neutrophil content with an enzyme marker
J Invest Dermatol
(1982) - et al.
Myeloperoxidase activity as a quantitative assessment of neutrophil infiltration into ischemic myocardium
J Pharmacol Methods
(1985)
Effects of dosmalfate, a new cytoprotective agent, on acute and chronic trinitrobenzene sulphonic acid-induced colitis in rats
Eur J Pharmacol
IL-6: a regulator of the transition from neutrophil to monocyte recruitment during inflammation
Trends Immunol
The pro- and anti-inflammatory properties of the cytokine interleukin-6
Biochim Biophys Acta
Interleukin-1beta mediates the extra-intestinal thrombosis associated with experimental colitis
Am J Pathol
The acute phase response
Immunol Today
Implication of TNF-related apoptosis inducing ligand in inflammatory intestinal epithelial lesions
Gastroenterology
MAPK signalling pathways as molecular targets for anti-inflammatory therapy—from molecular mechanisms to therapeutic benefits
Biochim Biophys Acta
Review article: the role of non-biological drugs in refractory inflammatory bowel disease
Aliment Pharmacol Ther
Novel drug delivery strategies for the treatment of inflammatory bowel disease
Expert Opin Drug Deliv
Cancer prevention and therapeutics. Panax ginseng
Altern Med Rev
Complementary and alternative medicine use among adults
Adv Data
Molecular mechanisms and clinical applications of ginseng root for cardiovascular disease
Med Sci Monit
Anti-amnestic and anti-aging effects of ginsenoside Rg1 and Rb1 and its mechanism of action
Acta Pharmacol Sin
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