Selective mGluR1 Negative Allosteric Modulator Reduces Blood-Brain Barrier Permeability and Cerebral Edema After Experimental Subarachnoid Hemorrhage.
Selective mGluR1 Negative Allosteric Modulator Reduces Blood-Brain Barrier Permeability and Cerebral Edema After Experimental Subarachnoid Hemorrhage.
复制标题
选择性 mGluR1 负变构调节剂可降低实验性蛛网膜下腔出血后的血脑屏障通透性和脑水肿。
DOI：
10.1007/s12975-019-00758-z
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发表时间：
2020
影响因子：
6.9
通讯作者：
Zhang Zong-Yong
中科院分区：
文献类型：
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作者：
Zhang Cheng;Jiang Ming;Wang Wei-Qi;Zhao Shi-Jun;Yin Yan-Xin;Mi Qiong-Jie;Yang Ming-Feng;Song Yu-Qiang;Sun Bao-Liang;Zhang Zong-Yong
血脑屏障（BBB）的破坏可导致血管源性脑水肿，并有助于蛛网膜下腔出血（SAH）后的早期脑损伤（EBI）。然而，SAH后血脑屏障损伤的机制尚不清楚。在这里，我们报道了脑脊液（CSF）的神经递质谷氨酸在伴有脑水肿症状的SAH患者中显著升高。通过大鼠SAH模型，我们发现SAH引起脑脊液谷氨酸水平升高和脑屏障通透性升高，脑室内注射外源性谷氨酸加重了脑屏障损伤和脑水肿，而腹腔注射代谢性谷氨酸受体1（mGluR1）阴性变弹性调节剂JNJ16259685可显著减轻SAH诱导的脑屏障损伤和脑水肿。在体外血脑屏障模型中，我们发现谷氨酸增加了人脑微血管内皮细胞（HBMEC）的单层通透性，而JNJ16259685在HBMEC中保留了谷氨酸损伤的血脑屏障完整性。机械上，谷氨酸下调血管扩张剂刺激磷酸化蛋白（VASP）的水平和磷酸化，降低紧密连接蛋白occludin，增加AQP4在SAH后72 h的表达。然而，JNJ16259685在SAH后72 h显著增加VASP、p-VASP和occludin，并降低AQP水平。总之，我们的研究结果表明，谷氨酸在破坏血脑屏障功能和JNJ16259685抑制mGluR1中发挥重要作用，减少了SAH后血脑屏障损伤和脑水肿。
The blood–brain barrier (BBB) disruption leads to the vasogenic brain edema and contributes to the early brain injury (EBI) after subarachnoid hemorrhage (SAH). However, the mechanisms underlying the BBB damage following SAH are poorly understood. Here we reported that the neurotransmitter glutamate of cerebrospinal fluid (CSF) was dramatically increased in SAH patients with symptoms of cerebral edema. Using the rat SAH model, we found that SAH caused the increase of CSF glutamate level and BBB permeability in EBI, intracerebroventricular injection of exogenous glutamate deteriorated BBB damage and cerebral edema, while intraperitoneally injection of metabotropic glutamate receptor 1(mGluR1) negative allosteric modulator JNJ16259685 significantly attenuated SAH-induced BBB damage and cerebral edema. In an in vitro BBB model, we showed that glutamate increased monolayer permeability of human brain microvascular endothelial cells (HBMEC), whereas JNJ16259685 preserved glutamate-damaged BBB integrity in HBMEC. Mechanically, glutamate downregulated the level and phosphorylation of vasodilator-stimulated phosphoprotein (VASP), decreased the tight junction protein occludin, and increased AQP4 expression at 72 h after SAH. However, JNJ16259685 significantly increased VASP, p-VASP, and occludin, and reduced AQP level at 72 h after SAH. Altogether, our results suggest an important role of glutamate in disruption of BBB function and inhibition of mGluR1 with JNJ16259685 reduced BBB damage and cerebral edema after SAH.