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.

中文翻译：

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负性变构调节剂mGluR1改善了实验性蛛网膜下腔出血后的长期神经功能缺陷。

动脉瘤性蛛网膜下腔出血（SAH）引起永久性神经系统后遗症，但其潜在机制有待进一步阐明。在这里，我们显示负变构调节剂JNJ16259685对代谢型谷氨酸受体1（mGluR1）的抑制作用改善了SAH血管内穿孔模型的长期神经行为结果。JNJ16259685通过抑制大鼠SAH模型中的脑血流量（CBF）减少，脑血管收缩和微血栓形成，改善了脑血管功能障碍。此外，JNJ16259685通过减轻神经元死亡和变性来减少SAH诱导的长期神经元损伤。在机械上，JNJ16259685维持内皮一氧化氮合酶（eNOS）和血管扩张剂刺激的磷蛋白（VASP）的磷酸化，并降低凋亡相关因子Bax，实验性SAH后可激活caspase-9和caspase-3。总之，我们的结果表明JNJ16259685通过神经血管保护改善了长期功能损伤。