The GluN1/GluN2B NMDA receptor and metabotropic glutamate receptor 1 negative allosteric modulator has enhanced neuroprotection in a rat subarachnoid hemorrhage model
The GluN1/GluN2B NMDA receptor and metabotropic glutamate receptor 1 negative allosteric modulator has enhanced neuroprotection in a rat subarachnoid hemorrhage model
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GluN1/GluN2B NMDA 受体和代谢型谷氨酸受体 1 负变构调节剂在大鼠蛛网膜下腔出血模型中增强神经保护作用
DOI：
10.1016/j.expneurol.2017.12.005
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发表时间：
2018
影响因子：
5.3
通讯作者：
Sun Baoliang
中科院分区：
文献类型：
--
作者：
Zhang Zongyong;Liu Junke;Fan Cundong;Mao Leilei;Xie Rongxia;Wang Suyun;Yang Mingfeng;Yuan Hui;Yang Xiaoyi;Sun Jingyi;Wang Jian;Kong Jiming;Huang Siluo;Sun Baoliang
蛛网膜下腔出血（SAH）后脑脊液中过量的谷氨酸通过钙超载和随后的凋亡级联反应引起兴奋性毒性损伤。含有N-甲基-D-天冬氨酸（NMDA）受体和代谢型谷氨酸受体1（mGluR 1）的GluN 1/GluN 2B在谷氨酸介导的兴奋毒性中起主导作用。在此，我们报告了艾芬地尔（100 μM）（GluN 1/GluN 2B NMDA受体的负变构调节剂（NAM））和JNJ 16259685（10 μM）（mGluR 1的NAM）对谷氨酸（100 μM）诱导的原代皮质、海马和小脑颗粒神经元中的Ca 2+释放和细胞凋亡具有相加效应。与艾芬地尔（10 mg/kg）和JNJ 16259685（1 mg/kg）单独腹腔注射相比，艾芬地尔和JNJ 16259685联合治疗可显著改善SAH后24 h和72 h的神经功能缺损。它减少了72 h时皮质和海马CA 1区TUNEL/DAPI阳性和活化caspase-3/NeuN阳性细胞的数量，降低了72 h时脑脊液中谷氨酸的水平，并降低了线粒体Ca 2+浓度。同时，联合治疗减弱凋亡，如在SAH后24 h增加Bcl-2表达，减少Bax表达和细胞色素c释放，以及减少裂解的caspase-9和caspase-3。这些发现表明，使用艾芬地尔和JNJ 16259685靶向细胞内Ca 2+超载和神经元凋亡是一种有希望的SAH新疗法。
Excessive glutamate in cerebrospinal fluid after subarachnoid hemorrhage (SAH) causes excitotoxic damage through calcium overloading and a subsequent apoptotic cascade. GluN1/GluN2B containingN-methyl-Daspartate (NMDA) receptor and metabotropic glutamate receptor 1 (mGluR1) can play a leading role in glutamate-mediated excitotoxicity. Here we report that Ifenprodil (100 μM), a negative allosteric modulator (NAM) of GluN1/GluN2B NMDA receptors, and JNJ16259685 (10 μM), a NAM of mGluR1, have an additive efficacy against glutamate (100 μM)-induced Ca2 +release and cell apoptosis in primary cortical, hippocampal, and cerebellar granule neurons. Compared with intraperitoneal injection of Ifenprodil (10 mg/kg) and JNJ16259685 (1 mg/kg) separately, the combination therapy of Ifenprodil plus JNJ16259685 significantly improves the neurological deficit at 24 h and 72 h after experimental SAH. It reduces the number of TUNEL/DAPI-positive and activated caspase-3/NeuN-positive cells in cortical and hippocampal CA1 regions at 72 h, decreases levels of glutamate in cerebrospinal fluid at 72 h, and reduces the mitochondrial Ca2 +concentration. Meanwhile, the combination therapy attenuates apoptosis as shown by an increased Bcl-2 expression, decreased Bax expression and release of cytochromec, and reduction of cleaved caspase-9 and caspase-3 at 24 h after SAH. These findings indicate that targeting both the intracellular Ca2 +overloading and neuronal apoptosis using the Ifenprodil and JNJ16259685 is a promising new therapy for SAH.