A novel caffeoyl triterpene attenuates cerebral ischemic injury with potent anti-inflammatory and hypothermic effects
A novel caffeoyl triterpene attenuates cerebral ischemic injury with potent anti-inflammatory and hypothermic effects
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一种新型咖啡酰三萜可减轻脑缺血损伤，具有有效的抗炎和降温作用
DOI：
10.1111/jnc.13046
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发表时间：
2015
影响因子：
4.7
通讯作者：
Zhang Hai Yan
中科院分区：
文献类型：
--
作者：
Ruan Zhi;Wang Hong Min;Huang Xiao Tian;Fu Yan;Wu Jian;Ye Chun Yan;Li Jin Long;Wu Lei;Gong Qi;Zhao Wei Min;Zhang Hai Yan
尽管在寻找卒中治疗方面付出了巨大努力，但仍然迫切需要探索具有高疗效和宽治疗时间窗的缺血性卒中新型神经保护剂。在这里，我们首次证明了28-O-咖啡酰桦木醇（B-CA），一种天然咖啡酰三萜的新型衍生物，在大鼠短暂性大脑中动脉闭塞后6小时给予，可以显著缓解脑梗死和神经功能缺损。此外，缺血后B-CA给药对脑梗死和功能（即，运动和感觉）缺陷。保护性B-CA作用与炎症反应减少相关，如抑制小胶质细胞和星形胶质细胞活化[分别用离子钙结合衔接分子1（Iba-1）和胶质细胞酸性蛋白（GFAP）抗体染色]以及抑制缺血大鼠同侧皮质中肿瘤坏死因子-α、白细胞介素-1 β和环氧合酶-2的过度产生所示。B‐CA给药导致局灶性脑缺血大鼠明显体温降低，这可能有助于其对脑损伤和炎症的改善作用。我们首次报道了28-O-咖啡酰白桦脂醇（B-CA），一种新的合成咖啡酰三萜，其灵感来自南蛇藤（Celastrus orbiculatus ThunB）的活性天然成分，具有强大的神经保护作用，对缺血性卒中具有广泛的临床有用的治疗时间窗，与抗炎和低温作用相关。因此，这种新的咖啡酰三萜衍生物可能导致发展有效的治疗策略，用于治疗缺血性中风。
Despite the intense efforts in searching for stroke therapies, an urgent need still exists to explore novel neuroprotective agents for ischemic stroke that have high efficacy and wide therapeutic time‐window. Here, we provide the first demonstration that 28‐O‐caffeoyl betulin (B‐CA), a novel derivative of naturally occurring caffeoyl triterpene, could significantly alleviate brain infarction and neurological deficit when given as late as 6 h after transient middle cerebral artery occlusion in the rat. Moreover, post‐ischemia B‐CA administration exhibited long‐term (14 days post stroke) protective effects on both brain infarction and functional (i.e., motor and sensory) deficits. Protective B‐CA effects correlated with decreased inflammatory responses as indicated by inhibition of microglia and astrocyte activation [stained with ionized calcium‐binding adapter molecule 1 (Iba‐1) and glial fibrillary acidic protein (GFAP) antibody, respectively], as well as suppression of tumor necrosis factor‐α, interleukin‐1β, and cyclooxygenase‐2 overproduction in the ipsilateral cortex of ischemic rat. B‐CA administration caused significant hypothermia in the focal cerebral ischemic rat, which may contribute to its ameliorative effects on brain damage and inflammation. In view of its potency in wide therapeutic time‐window, robust anti‐inflammatory and hypothermic effects, this novel caffeoyl triterpene derivative may lead toward the development of effective therapeutic strategies for the treatment of ischemic stroke.We documented for the first time that 28‐O‐caffeoyl betulin (B‐CA), a novel synthetic caffeoyl triterpene inspired from active natural principles ofCelastrus orbiculatusThunb, possessed robust neuroprotection with a wide and clinically useful therapeutic time window against ischemic stroke, correlating with the anti‐inflammatory and hypothermic effects. Thus, this novel caffeoyl triterpene derivative may lead toward the development of effective therapeutic strategies for the treatment of ischemic stroke.