Eupatilin exerts neuroprotective effects in mice with transient focal cerebral ischemia by reducing microglial activation.
Eupatilin exerts neuroprotective effects in mice with transient focal cerebral ischemia by reducing microglial activation.
复制标题
DOI：
10.1371/journal.pone.0171479
复制
发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Choi JW
中科院分区：
文献类型：
--
作者：
Sapkota A;Gaire BP;Cho KS;Jeon SJ;Kwon OW;Jang DS;Kim SY;Ryu JH;Choi JW
小胶质细胞活化及其驱动的神经炎症是包括局灶性脑缺血在内的神经系统疾病的特征性病理特征。众所周知，亚洲蒿（菊科）提取物及其活性成分eupatilin可减少炎症反应。但是，eupatilin对抗局灶性脑缺血的治疗潜力沿着其对激活的小胶质细胞的抗炎活性尚不清楚。在这项研究中，我们研究了Eupatilin对局灶性脑缺血的神经保护作用，通过其抗炎作用，特别是对激活的小胶质细胞，采用短暂的大脑中动脉闭塞/再灌注（tMCAO），结合脂多糖刺激的BV 2小胶质细胞。Eupatilin在活化的BV 2小胶质细胞中发挥抗炎反应，其中它以浓度依赖性方式减少众所周知的炎症标志物（包括亚硝酸盐、IL-6、TNF-α和PGE 2）的分泌。这些在体外观察到的效果，eupatilin导致在体内的神经保护局灶性脑缺血。在tMCAO攻击的小鼠中，在治疗范例中口服给予eupatilin（10 mg/kg）显著减少脑梗死并改善神经功能。当甚至在MCAO诱导后5小时内给予eupatilin时也观察到相同的益处。此外，在tMCAO激发后立即单次给予eupatilin（10 mg/kg）的神经保护作用持续至tMCAO后3天。Eupatilin给药减少了缺血脑中Iba 1免疫阳性细胞的数量，并诱导其在缺血核心中从变形样变为分枝状的形态学变化，这伴随着缺血脑中小胶质细胞增殖的减少。Eupatilin通过减少IKKα/β磷酸化、IκBα磷酸化和IκBα降解抑制缺血脑中NF-κB信号传导活性。总体而言，这些数据表明，eupatilin是一种神经保护剂，通过减少小胶质细胞的激活，对抗局灶性脑缺血。
Microglial activation and its-driven neuroinflammation are characteristic pathogenetic features of neurodiseases, including focal cerebral ischemia. The Artemisia asiatica (Asteraceae) extract and its active component, eupatilin, are well-known to reduce inflammatory responses. But the therapeutic potential of eupatilin against focal cerebral ischemia is not known, along with its anti-inflammatory activities on activated microglia. In this study, we investigated the neuroprotective effect of eupatilin on focal cerebral ischemia through its anti-inflammation, particularly on activated microglia, employing a transient middle cerebral artery occlusion/reperfusion (tMCAO), combined with lipopolysaccharide-stimulated BV2 microglia. Eupatilin exerted anti-inflammatory responses in activated BV2 microglia, in which it reduced secretion of well-known inflammatory markers, including nitrite, IL-6, TNF-α, and PGE2, in a concentration-dependent manner. These observed in vitro effects of eupatilin led to in vivo neuroprotection against focal cerebral ischemia. Oral administration of eupatilin (10 mg/kg) in a therapeutic paradigm significantly reduced brain infarction and improved neurological functions in tMCAO-challenged mice. The same benefit was also observed when eupatilin was given even within 5 hours after MCAO induction. In addition, the neuroprotective effects of a single administration of eupatilin (10 mg/kg) immediately after tMCAO challenge persisted up to 3 days after tMCAO. Eupatilin administration reduced the number of Iba1-immunopositive cells across ischemic brain and induced their morphological changes from amoeboid into ramified in the ischemic core, which was accompanied with reduced microglial proliferation in ischemic brain. Eupatilin suppressed NF-κB signaling activities in ischemic brain by reducing IKKα/β phosphorylation, IκBα phosphorylation, and IκBα degradation. Overall, these data indicate that eupatilin is a neuroprotective agent against focal cerebral ischemia through the reduction of microglial activation.