CCR5 deficiency accelerates lipopolysaccharide-induced astrogliosis, amyloid-beta deposit and impaired memory function.

Chemokine receptors are implicated in inflammation and immune responses. Neuro-inflammation is associated with activation of astrocyte and amyloid-beta (Aß) generations that lead to pathogenesis of Alzheimer disease (AD). Previous our study showed that deficiency of CC chemokine receptor 5 (CCR5) results in activation of astrocytes and Aß deposit, and thus memory dysfunction through increase of CC chemokine receptor 2 (CCR2) expression. CCR5 knockout mice were used as an animal model with memory dysfunction. For the purpose LPS was injected i.p. daily (0.25 mg/kg/day). The memory dysfunctions were much higher in LPS-injected CCR5 knockout mice compared to CCR5 wild type mice as well as non-injected CCR5 knockout mice. Associated with severe memory dysfuction in LPS injected CCR5 knockout mice, LPS injection significant increase expression of inflammatory proteins, astrocyte activation, expressions of ß-secretase as well as Aß deposition in the brain of CCR5 knockout mice as compared with that of CCR5 wild type mice. In CCR5 knockout mice, CCR2 expressions were high and co-localized with GFAP which was significantly elevated by LPS. Expression of monocyte chemoattractant protein-1 (MCP-1) which ligands of CCR2 also increased by LPS injection, and increment of MCP-1 expression is much higher in CCR5 knockout mice. BV-2 cells treated with CCR5 antagonist, D-ala-peptide T-amide (DAPTA) and cultured astrocytes isolated from CCR5 knockout mice treated with LPS (1 µg/ml) and CCR2 antagonist, decreased the NF-ĸB activation and Aß level. These findings suggest that the deficiency of CCR5 enhances response of LPS, which accelerates to neuro-inflammation and memory impairment.

Anti-inflammatory effect of tricin 4'-O-(threo-ß-guaiacylglyceryl) ether, a novel flavonolignan compound isolated from Njavara on in RAW264.7 cells and in ear mice edema.

Although recent study has shown tricin 4'-O-(threo-ß-guaiacylglyceryl) ether (TTGE), an isolated compound from Njavara rice, to have the most potent anti-inflammatory effects, the action mechanism has not been fully understood. Here, we examined the effect of TTGE on the inflammation and elucidated the potential mechanism. We demonstrated that TTGE significantly inhibited LPS-induced NO and ROS generation in RAW264.7 cells, which was correlated with the down-regulating effect of TTGE on the iNOS and COX-2 expression via NF-κB and STAT3. TPA-induced ear edema was also efficiently inhibited by the TTGE treatment. TTGE blocked the induction of iNOS and COX-2 through the regulation of NF-κB and STAT3, which could explain the reduced TPA-induced edema symptoms. Moreover, the introduction of ERK inhibitor abrogated the anti-inflammatory effect of TTGE via the recovery of NF-κB and STAT3 signalings. Taken together, these results suggest that TTGE has anti-inflammatory properties through down-regulation of NF-κB and STAT3 pathways.