Department of Neurology, Second Affiliated Hospital; Key Laboratory of Cerebral Microcirculation, Shandong First Medical University & Shandong Academy of Medical Sciences, Taian 271016, Shandong, People's Republic of China.
Department of Neurology, Medical College of Qingdao University, Qingdao 266021, Shandong, People's Republic of China.
ACS Chem Neurosci. 2020 Sep 16;11(18):2869-2880. doi: 10.1021/acschemneuro.0c00485. Epub 2020 Aug 25.
Aneurysmal subarachnoid hemorrhage (SAH) causes permanent neurological sequelae, but the underlying mechanism needs to be further clarified. Here, we show that inhibition of metabotropic glutamate receptor 1 (mGluR1) with negative allosteric modulator JNJ16259685 improves long-term neurobehavioral outcomes in an endovascular perforation model of SAH. JNJ16259685 improves cerebrovascular dysfunction through attenuation of cerebral blood flow (CBF) reduction, cerebral vasoconstrictio, and microthrombosis formation in a rat SAH model. Moreover, JNJ16259685 reduces experimental SAH-induced long-term neuronal damage through alleviation of neuronal death and degeneration. Mechanically, JNJ16259685 maintains phosphorylation of endothelial NO synthase (eNOS) and vasodilator-stimulated phosphoprotein (VASP) and decreases apoptosis-related factors Bax, active caspase-9, and active caspase-3 following experimental SAH. Altogether, our results suggest JNJ16259685 improves long-term functional impairment through neurovascular protection.
颅内动脉瘤性蛛网膜下腔出血（SAH）可导致永久性神经后遗症，但发病机制尚需进一步阐明。在这里，我们发现，代谢型谷氨酸受体 1（mGluR1）的负变构调节剂 JNJ16259685 抑制作用可改善 SAH 血管内穿孔模型的长期神经行为结局。JNJ16259685 通过减轻脑血流量（CBF）减少、脑血管收缩和微血栓形成来改善脑血管功能障碍在大鼠 SAH 模型中。此外，JNJ16259685 通过减轻神经元死亡和变性来减少实验性 SAH 诱导的长期神经元损伤。从机制上讲，JNJ16259685 可维持内皮型一氧化氮合酶（eNOS）和血管扩张刺激磷蛋白（VASP）的磷酸化，并在实验性 SAH 后降低凋亡相关因子 Bax、活性半胱天冬酶-9 和活性半胱天冬酶-3。综上所述，我们的研究结果表明，JNJ16259685 通过神经血管保护改善长期功能障碍。
