Department of Neurological Surgery, Vanderbilt University Medical Center, Nashville, TN, USA.
Department of General Surgery, Beijing Shijitan Hospital, Capital Medical University, China.
Eur J Pharmacol. 2021 Jun 5;900:174038. doi: 10.1016/j.ejphar.2021.174038. Epub 2021 Mar 16.
Subarachnoid hemorrhage (SAH) due to rupture of an intracranial aneurysm leads to vasospasm resulting in delayed cerebral ischemia. Therapeutic options are currently limited to hemodynamic optimization and nimodipine, which have marginal clinical efficacy. Nitric oxide (NO) modulates cerebral blood flow through activation of the cGMP-Protein Kinase G (PKG) pathway. Our hypothesis is that SAH results in downregulation of signaling components in the NO-PKG pathway which could explain why treatments for vasospasm targeting this pathway lack efficacy and that treatment with a cell permeant phosphopeptide mimetic of downstream effector prevents delayed vasospasm after SAH. Using a rat endovascular perforation model, reduced levels of NO-PKG pathway molecules were confirmed. Additionally, it was determined that expression and phosphorylation of a PKG substrate: Vasodilator-stimulated phosphoprotein (VASP) was downregulated. A family of cell permeant phosphomimetic of VASP (VP) was wasdesigned and shown to have vasorelaxing property that is synergistic with nimodipine in intact vascular tissuesex vivo. Hence, treatment targeting the downstream effector of the NO signaling pathway, VASP, may bypass receptors and signaling elements leading to vasorelaxation and that treatment with VP can be explored as a therapeutic strategy for SAH induced vasospasm and ameliorate neurological deficits.
颅内动脉瘤破裂导致的蛛网膜下腔出血 (SAH) 可导致血管痉挛，进而引发迟发性脑缺血。目前的治疗选择仅限于血流动力学优化和尼莫地平，但其临床疗效有限。一氧化氮 (NO) 通过激活 cGMP-蛋白激酶 G (PKG) 途径来调节脑血流。我们的假设是，SAH 导致 NO-PKG 途径中的信号转导成分下调，这可以解释为什么针对该途径的血管痉挛治疗缺乏疗效，以及用一种穿透细胞膜的 PKG 下游效应物磷酸肽模拟物治疗可以预防 SAH 后的迟发性血管痉挛。通过大鼠血管内穿孔模型，证实了 NO-PKG 途径分子水平降低。此外，还确定了 PKG 底物：血管舒张刺激磷蛋白 (VASP) 的表达和磷酸化下调。设计了一组穿透细胞膜的 VASP 磷酸肽模拟物 (VP)，并证明其具有血管舒张特性，在完整的血管组织中与尼莫地平具有协同作用。因此，针对 NO 信号通路下游效应物 VASP 的治疗方法可能绕过受体和信号元件，从而实现血管舒张，并且可以探索用 VP 治疗作为治疗 SAH 引起的血管痉挛和改善神经功能缺损的治疗策略。
