The Role of κ Opioid Receptor in Brain Ischemia.
The Role of κ Opioid Receptor in Brain Ischemia.
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DOI：
10.1097/ccm.0000000000001959
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发表时间：
2016-12
影响因子：
8.8
通讯作者：
Liu R
中科院分区：
文献类型：
--
作者：
Chen C;Xi C;Liang X;Ma J;Su D;Abel T;Liu R
我们前期的研究表明，高选择性κ阿片受体激动剂具有脑保护作用，提示KOR激动剂在脑缺血中具有重要作用。在这项研究中，我们研究了在大脑中动脉闭塞（MCAO）小鼠模型的脑缺血的作用和相关机制的KOR激动剂。雄性成年小鼠脑缺血120 min再灌注24 h建立MCAO模型。不同剂量的鼠尾草素A（SA），一种高度选择性和有效的KOR激动剂，鼻内给药后10分钟开始再灌注。Norbinaltorphimine（2.5mg/kg，i.p.）作为KOR拮抗剂，在SA（50 µg/kg）给药前在一组中给药，以研究KOR的特定作用。再灌注24 h后测定神经行为学指标。测定脑CT容积、KOR表达和脑内伊文思蓝外渗。采用免疫组化和western blot检测caspase-3、IL-10和TNF-α的活化水平，探讨细胞凋亡和炎症的作用。缺血半暗带区KOR表达较非缺血区明显升高。SA剂量依赖性地减少梗死体积和改善神经功能缺损。50 µg/kg剂量的SA减少了伊文思蓝外渗，表明血脑屏障受损减轻，并降低了半影区裂解的酪蛋白酶-3，IL-10和TNF-α的表达。所有这些变化都被norbinaltorphimine阻断或减轻。KOR表达上调，在脑缺血再灌注过程中起重要作用。KOR激活可能通过保护血脑屏障、减少细胞凋亡和抑制炎症来保护大脑并改善神经功能。
Our previous studies indicated that highly selective kappa opioid receptor (KOR) agonists could protect the brain, indicating an important role of KOR agonist in brain ischemia. In this study, we investigated the role and related mechanisms of KOR agonists in brain ischemia in a middle cerebral artery occlusion (MCAO) mouse model. The MCAO model was established by 120 minutes of ischemia followed by 24 h reperfusion in male adult mice. Various doses of salvinorin A (SA), a highly selective and potent KOR agonist, were administered intranasally 10 min after initiation of reperfusion. Norbinaltorphimine (2.5 mg/kg, i.p.) as a KOR antagonist was administered in one group before administration of SA (50 µg/kg) to investigate the specific role of KOR. After 24 h reperfusion, neurobehavioral outcome was determined. Infarct volume, KOR expression, and Evans blue extravasation in the brain were determined. Immunohistochemistry and western blot were performed to detect the activated caspase-3, IL-10 and TNF-alpha levels to investigate the role of apoptosis and inflammation. KOR expression was elevated significantly in the ischemic penumbral area compared to that in the non-ischemic area. SA reduced infarct volume and improved neurological deficits dose-dependently. SA at the dose of 50 µg/kg reduced Evans blue extravasation, suggesting reduced impairment of the blood-brain barrier, and decreased the expression of cleaved casepase-3, IL-10 and TNF-alpha in the penumbral areas. All these changes were blocked or alleviated by norbinaltorphimine. KORs were up-regulated and played a critical role in brain ischemia and reperfusion. KOR activation could potentially protect the brain and improve neurological outcome via blood brain barrier protection, apoptosis reduction and inflammation inhibition.