Effects of fimasartan, one of angiotensin receptor blockers, on tissue damages and inflammation after focal ischemia in rat brain

Abstract

Background and Purpose: Fimasartan is a newly developed angiotensin receptor blocker (ARB), and evidences suggests that fimasartan may have protective effects during myocardial infarction or atherosclerosis. However, the application of regular-dose ARBs during ischemic stroke should be used cautiously (due to lessons learned from other ARBs). In this context, we investigated the effects of low-dose fimasartan on tissue damage and inflammation after focal ischemia in rat brain.

Materials and Methods: To evaluate anti-inflammatory effects of fimasartan, oxygen-glucose deprivation (OGD) was applied in cultured astrocytes and fimasartan was treated. In in vivo experiments, noninvasive blood pressure monitoring was performed in Sprague-Dawley rats which fimasartan or phosphate-buffered saline (PBS) were administered for 4 weeks. A low-dose (0.5 mg/kg) and regular doses (1 or 3 mg/kg) of fimasartan was administered intraorally for 4 weeks, and we induced ischemia-reperfusion injury in rats. Infarct volume and the number of TUNEL-positive apoptotic cells were measured at 7 days. Functional outcomes were evaluated by modified limb placing test. To identify the anti-inflammatory effect of fimasartan, the number of inflammatory cells (OX6-positive cells) was measured. To evaluate inflmmatory makers, IkB and cyclooxygenase-2 (COX-2) were measured via Western blot analyses at 48 hours. Especially for low-dose fimasartan (0.5 mg/kg), the effects of post-treated fimasartan on infarct volume was also evaluated.

Results: During OGD, fimasartan reduced the inflammatory markers in astrocytes: nuclear translocation of NF-κB, degradation of IκB, and expression of COX-2. After the administration of low-dose (0.5 mg/kg) fimasartan, blood pressure did not decrease compared to the phosphate-buffered saline (PBS)-control with MCA occlusion (MCAO) group. The infarct volume and ischemic cell death were reduced in the low-dose fimasartan-treated group (46 ± 41 for 0.5 mg/kg and 153 ± 47 mm3 for PBS-control with MCAO

P < 0.01) but not in the regular-dose groups. Low-dose fimasartan treatment improved functional recovery after ischemia and significantly decreased mortality. In our study, fimasartan reduced the degradation of IκB (whose degradation is a marker for NF-κB activation) and the formation of an inflammatory end-product, COX-2. As a result, the recruitment of inflammatory cells in the peri-infarct area decreased after low-dose, long-term treatment. After induction of transient MCAO, low dose fimasartan (0.5 mg/kg) was administerd for 3 days per oral route. The infarct volume at 3 days after MCAO decreased significantly in low-dose post-treated group compare to PBS-control with MCAO (110.8 ± 46.1 versus 162.7 ± 42.3 mm3

P < 0.05).

Conclusion: We have demonstrated that low-dose, long-term fimasartan pre-treatment improved outcomes after focal ischemia in the brain via a reduction of inflammation. These low-dose fimasartan may have beneficial effects on tissue damage in post-treatment after MCAO.