Anti-inflammatory effects of fimasartan via Akt, ERK, and NF kappa B pathways on astrocytes stimulated by hemolysate

作者：Yang Xiu Li; Kim Chi Kyung; Kim Tae Jung; Sun Jing; Rim Doeun; Kim Young Ju; Ko Sang Bae; Jang Hyunduk; Yoon Byung Woo

来源：Inflammation Research, 2016, 65(2): 115-123.

DOI：10.1007/s00011-015-0895-9

• Fimasartan
• Hemolysate
• Intracerebral hemorrhage
• Inflammation
• Astrocyte

The aim of this study was to investigate whether fimasartan, a novel angiotensin II receptor blocker, modulates hemolysate-induced inflammation in astrocytes.
We stimulated astrocytes with hemolysate to induce hemorrhagic inflammation in vitro. Astrocytes were pretreated with fimasartan and then incubated with hemolysate at different durations. Anti-inflammatory cell signaling molecules including Akt, extracellular signal regulated kinase (ERK), NF kappa B and cyclooxygenase-2 (COX-2) were assessed by western blotting. Pro-inflammatory mediators were evaluated by real-time RT-PCR and ELISA.
The stimulation by hemolysate generated a robust activation of inflammatory signaling pathways in astrocytes. Hemolysate increased the phosphorylation of Akt at 1 h, and ERK1/2 at 20 min compared with the control group and promoted the degradation of I kappa B alpha. Pretreated fimasartan significantly decreased hemolysate-induced phosphorylation of Akt and ERK1/2. In addition, fimasartan also suppressed NF kappa B-related inflammatory pathways induced by hemolysate, including reduction of the gene expression of NF kappa B, and decreased nuclear translocation of NF kappa B and degradation of I kappa B. This reduction of inflammatory upstream pathways decreased the expression of inflammatory end-products: COX-2 and interleukin-1 (IL-1 beta). Furthermore, the expression of COX-2 was attenuated by both Akt inhibitor (LY294002) and ERK inhibitor (U0126), and I kappa B alpha degradation was suppressed by LY294002.
These results demonstrate that pretreatment with fimasartan to astrocytes suppresses the inflammatory responses induced by hemolysate. Akt, ERK and NF kappa B were associated with hemolysate-induced COX-2 and IL-1 beta expression. Based on these mechanisms, fimasartan could be a candidate anti-inflammatory regulator for the treatment of intracerebral hemorrhage.

• 出版日期2016-2