白杨素通过可溶性环氧化物水解酶和环氧二十碳三烯酸保护大鼠免受脑缺血损伤。
Pinocembrin protects rats against cerebral ischemic damage through soluble epoxide hydrolase and epoxyeicosatrienoic acids.
机构信息
Beijing Key Laboratory of Drug Target Identification and Drug Screening, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
出版信息
Chin J Nat Med. 2013 May;11(3):207-13. doi: 10.1016/S1875-5364(13)60018-7.
AIM
To investigate the relationship between cerebroprotection of pinocembrin and epoxyeicosatrienoic acids (EETs) and their regulating enzyme soluble epoxide hydrolase (sEH).
METHODS
Rats underwent middle cerebral artery occlusion (MCAO) to mimic permanent focal ischemia, and pinocembrin was administrated via tail vein injection at 10 min, 4 h, 8 h and 23 h after MCAO. After 24 MCAO, rats were re-anesthetized, and the blood and brain were harvested and analyzed.
RESULTS
Pinocembrin displayed significant protective effects on MCAO rats indicated by reduced neurological deficits and infarct volume. Importantly, co-administration of 0.2 mg·kg(-1) 14, 15-EEZE, a putative selective EET antagonist, weakened the beneficial effects of pinocembrin. 14, 15-EET levels in the blood and brain of rats after 24 h MCAO were elevated in the presence of pinocembrin. In an assay for hydrolase activity, pinocembrin significantly lowered brain sEH activity of MCAO rats and inhibited recombinant human sEH activity in a concentration-dependent manner (IC50, 2.58 μmol·L(-1)). In addition, Western blot and immunohistochemistry analysis showed that pinocembrin at doses of 10 mg·kg(-1) and 30 mg·kg(-1) significantly down-regulated sEH protein in rat brain, especially the hippocampus CA1 region of MCAO rats.
CONCLUSION
Inhibiting sEH and then increasing the potency of EETs may be one of the mechanisms through which pinocembrin provides cerebral protection.
目的
研究白杨素对环氧二十碳三烯酸（EETs）及其调节酶可溶性环氧化物水解酶（sEH）的脑保护作用与二者的关系。
方法
采用大脑中动脉闭塞（MCAO）大鼠模型模拟永久性局灶性缺血，在 MCAO 后 10 min、4 h、8 h 和 23 h 通过尾静脉注射给予白杨素。MCAO 后 24 h 再次麻醉大鼠，采集血液和脑组织并进行分析。
结果
白杨素可显著减轻 MCAO 大鼠的神经功能缺损和梗死体积，提示其具有保护作用。重要的是，同时给予 0.2 mg·kg(-1) 14, 15-EEZE（一种潜在的选择性 EET 拮抗剂）可减弱白杨素的有益作用。MCAO 后 24 h 大鼠血液和脑组织中的 14, 15-EET 水平在存在白杨素的情况下升高。在水解酶活性测定中，白杨素显著降低 MCAO 大鼠脑 sEH 活性，并呈浓度依赖性抑制重组人 sEH 活性（IC50 为 2.58 μmol·L(-1)）。此外，Western blot 和免疫组织化学分析显示，白杨素在 10 mg·kg(-1)和 30 mg·kg(-1)剂量下可显著下调 MCAO 大鼠脑 sEH 蛋白，尤其是海马 CA1 区。
结论
抑制 sEH 进而增强 EETs 的效力可能是白杨素提供脑保护的机制之一。
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