Anti-Inflammatory Mechanism of Compound K in Activated Microglia and Its Neuroprotective Effect on Experimental Stroke in Mice

Abstract

Microglial activation plays a pivotal role in the pathogenesis of various neurologic disorders, such as cerebral ischemia, Alzheimer's disease, and Parkinson's disease. Thus, controlling microglial activation is a promising therapeutic strategy for such brain diseases. In the present study, we found that a ginseng saponin metabolite, compound K [20-O-D-glucopyranosyl-20(S)-protopanaxadiol], inhibited the expressions of inducible nitric-oxide synthase, proinflammatory cytokines, monocyte chemotactic protein-1, matrix metalloproteinase-3, and matrix metalloproteinase-9 in lipopolysaccharide (LPS)-stimulated BV2 microglial cells and primary cultured microglia. Subsequent mechanistic studies revealed that compound K suppressed microglial activation via inhibiting reactive oxygen species, mitogen-activated protein kinases, and nuclear factor-B/ activator protein-1 activities with enhancement of heme oxygenase-1/antioxidant response element signaling. To address the anti-inflammatory effects of compound K in vivo, we used two brain disease models of mice: sepsis (systemic inflammation) and cerebral ischemia. Compound K reduced the number of Iba1-positive activated microglia and inhibited the expressions of tumor necrosis factor-␣ and interleukin-1␤ in the LPS-induced sepsis brain. Furthermore, compound K reduced the infarct volume of ischemic brain induced by middle cerebral artery occlusion and suppressed microglial activation in the ischemic cortex. The results collectively suggest that compound K is a promising agent for prevention and/or treatment of cerebral ischemia and other neuroinflammatory disorders.

Lonicera japonicaTHUNB. Extract Inhibits Lipopolysaccharide-Stimulated Inflammatory Responses by Suppressing NF-κB Signaling in BV-2 Microglial Cells

“…35 Thus, controlling microglia-mediated MMP-9 production has been suggested as a possible therapeutic approach to treat CNS inflammation. 5,36 Several recent reports have demonstrated that natural products can inhibit MMP-9 and are thus considered to be potential therapeutic agents for alleviating neurodegenerative diseases. 37,38 In the present study, we investigated the effect of LJ on production of MMP-9 in LPS-stimulated BV-2 microglial cells.…”

Visceral adipose tissue inflammation is associated with age-related brain changes and ischemic brain damage in aged mice

“…Two serial brain sections from each animal were used, and quantification was performed in three different areas (500 lm 2 ) of the lateral cortex in the right hemisphere for each brain section. The mean cell number for six 500-lm 2 areas was calculated for each animal (Park et al, 2012).…”

Ginsenoside metabolite compound K exerts anti-inflammatory effect via suppressing T cell activation

“…CK markedly cured gram-negative bacterial-induced lethal shock via inhibiting systemic inflammatory cytokine production and reversing the lethal sequelae of sepsis [6] . CK decreased the number of activated microglia and reduced TNF-α and IL-1β levels in the LPS-induced sepsis brain [8] . CK alleviated colitis and suppressed the inflammation by inhibiting NF-κB activation [9] .…”

“…suppressed the activation of reactive oxygen species (ROS), MAPK, and NF-κB/activator protein-1(AP-1), and activated heme oxygenase-1(HO-1)/antioxidant response element (ARE) signaling [8] .…”