Ginsenoside Rh1 potentiates dexamethasone’s anti-inflammatory effects for chronic inflammatory disease by reversing dexamethasone-induced resistance

Abstract

IntroductionAcquired resistance to glucocorticoids constitutes a major clinical challenge, often overlooked in the search for compounds to improve the effect of classic steroids. We sought to unravel how a plant-original compound, ginsenoside Rh1, potentiates dexmethasone (DEX)’s potential anti-inflammation properties.MethodsGinsenoside Rh1 combined with DEX was applied in a short-term and long-term treatment protocol for inflammation. Its potential mechanism on anti-inflammation was explored. In addition, the effect of Rh1 on the side-effect induced by DEX was studied. Furthermore, the in vivo anti-inflammatory effects of Rh1 combined with DEX were evaluated in a collagen-induced arthritis (CIA) mice model.ResultsGinsenoside Rh1 potentiates DEX’s anti-inflammatory effects even after prolonged DEX treatment. Rh1 could improve the glucocorticoid receptor (GR)’s transrepression on nuclear factor kappa B (NF-κB) and transactivation on dual specificity protein phosphatase 1 (DUSP1), which is responsible for DEX’s anti-inflammatory effects. Parallel Western blot assay and radioligand binding analysis revealed that Rh1 could increase the expression and binding of GR. This is in sharp contrast to DEX alone, showing a direct link among prolonged treatment, decreasing GR and the abolishment of anti-inflammation. Interestingly, Rh1 does not enhance the transactivation of glucocorticoid-responsive elements (GRE) driven genes - gluconeogenic enzyme glucose-6-phosphatase (G6P) and phosphoenolpyruvate carboxykinasee phosphatase (PEPCK) in primary mouse hepatocytes, a mechanism partly held accountable for the metabolic side-effects. Similar results were found in CIA mice.ConclusionRh1 could potentiate DEX’s anti-inflammatory effects and does not cause a hyperglycemic side effect. Ginsenoside Rh1 combined with DEX may be a promising candidate treatment option for chronic inflammatory diseases in need of long-term immunosuppression therapies.

Ginsenoside Rh1: A Systematic Review of Its Pharmacological Properties

“…Topically applied 0.01 and 0.05 % G-Rh1 potently reduced the ear thickness in 12-O-tetradecanoylphorbol-13-acetate-and oxazolone-induced mouse dermatitis models and lowered the expression levels of COX-2, IL-1β, and TNF-α [49]. When combined with dexamethasone, G-Rh1 (10 mg/ kg) showed superior anti-inflammatory potential with a lower mean clinical severity in comparison with dexamethasone alone in collagen-induced arthritis mouse model [22].…”

“…He et al [34] reported no significant effect of G-Rh1 in the range of 0.1-10 µM on the activity of NF-κB luciferase reporter activity in human embryonic kidney 293 (HEK 293) cells induced by TNF-α (10 ng/mL). However, significant inhibition of NF-κB activation by G-Rh1 was also reported in HEK 293 cells pretreated with TNF-α [35], in BV2 glioma cells induced by LPS [36] or IFN-γ [37], in macrophages stimulated by LPS or TNBS [38], and in murine macrophage RAW 264.7 cells treated with LPS [39] or TNF-α [22]. Both He et al [34] and Xing et al [35] assessed the protective effect of G-Rh1 on the activation of NF-κB on HEK 293 cells induced by TNF-α.…”

“…There was no general conclusion for quality of the whole study. There are six studies that claimed the animals were divided randomly [22,44,50,58,59,70]. However, no study presented any method to generate the allocation sequence.…”

“…This compound has been additionally reported to effectively stimulate the central nervous system and enhance mental acuity and intellectual performance [20]. Several studies have shown that G-Rh1 possesses neuroprotective effects, potential antineoplastic effects, and the ability to be adjuvant therapy in chronic inflammatory diseases to dexamethasone [21][22][23]. Nonetheless, there is no critically evaluated review of the pharmacological effects of G-Rh1 based on summarizing the current reliable evidence.…”

“…In THP-1 cells, G-Rh1 did not only inactivate ERK1/2, but also attenuated the phosphorylation and activation of MAPK signaling, p38MAPK and JNK activation of PKB/Akt through lowering the expression of MCP-1 and CCR2, and deactivating integrins, the fibronectin receptor VLA-5 and CD29 [21]. Li et al [22] found that after long-term dexamethasone treatment in RAW264.7 cells, it also induced the activation of DUSP1, resulting in the downregulation of proinflammatory cytokines (IL-6, IL-17, MMP-1, TNF-α). On THP-1 cells, the effects seemed to depend on the concentrations of G-Rh1 and stimuli, namely, LPS and PMA [41].…”