Peripheral anti-inflammatory effects explain the ginsenosides paradox between poor brain distribution and anti-depression efficacy

Background: The effectiveness of ginseng in preventing and treating various central nervous system (CNS) diseases has been widely confirmed. However, ginsenosides, the principal components of ginseng, are characterized by poor accessibility to the brain, and this pharmacokinetic-pharmacological paradox remains poorly explained. Anti-inflammatory approaches are becoming promising therapeutic strategies for depression and other CNS diseases; however, previous studies have focused largely on anti-inflammatory therapies directed at the central nervous system. It is thus of interest to determine whether ginsenosides, characterized by poor brain distribution, are also effective in treating lipopolysaccharide (LPS) induced depression-like behavior and neuroinflammation. Methods: In an LPS-induced depression-like behavior model, the antidepressant effects of ginseng total saponins (GTS) were assessed using a forced swimming test, a tail suspension test, and a sucrose preference test. The anti-inflammatory efficacies of GTS in brain, plasma, and LPS-challenged RAW264.7 cells were validated using ELISA and quantitative real-time PCR. Moreover, indoleamine 2,3-dioxygenase (IDO) activity in the periphery and brain were also determined by measuring levels of kynurenine/tryptophan. Results: GTS significantly attenuated LPS-induced depression-like behavior. Moreover, LPS-induced increases in 5-HT and tryptophane turnover in the brain were significantly reduced by GTS. IDO activities in brain and periphery were also suppressed after pretreatment with GTS. Furthermore, GTS-associated recovery from LPS-induced depression-like behavior was paralleled with reduced mRNA levels for IL-1 beta, IL-6, TNF-alpha, and IDO in hippocampus. Poor brain distribution of ginsenosides was confirmed in LPS-challenged mice. GTS treatment significantly decreased production of various proinflammatory cytokines in both LPS-challenged mice and RAW264.7 cells. Conclusion: This study suggests that the anti-depression efficacy of GTS may be largely attributable to its peripheral anti-inflammatory activity. Our study also strengthens an important notion that peripheral anti-inflammation strategies may be useful in the therapy of inflammation-related depression and possibly other CNS diseases.