Department of Neurological Surgery, Washington University School of Medicine, 660 S Euclid Avenue, St Louis, MO 63110, USA.
Stroke. 2011 Mar;42(3):776-82. doi: 10.1161/STROKEAHA.110.607200. Epub 2011 Feb 11.
Vasospasm-induced delayed cerebral ischemia remains a major source of morbidity in patients with aneurysmal subarachnoid hemorrhage (SAH). We hypothesized that activating innate neurovascular protective mechanisms by preconditioning (PC) may represent a novel therapeutic approach against SAH-induced vasospasm and neurological deficits and, secondarily, that the neurovascular protection it provides is mediated by endothelial nitric oxide synthase (eNOS).
Wild-type mice were subjected to hypoxic PC or normoxia followed 24 hours later by SAH. Neurological function was analyzed daily; vasospasm was assessed on post-surgery Day 2. Nitric oxide availability, eNOS expression, and eNOS activity were also assessed. In a separate experiment, wild-type and eNOS-null mice were subjected to hypoxic PC or normoxia followed by SAH and assessed for vasospasm and neurological deficits.
PC nearly completely prevented SAH-induced vasospasm and neurological deficits. It also prevented SAH-induced reduction in nitric oxide availability and increased eNOS activity in mice with and without SAH. PC-induced protection against vasospasm and neurological deficits was lost in wild-type mice treated with the nitric oxide synthase inhibitor N(G)-nitro-l-arginine methyl ester and in eNOS-null mice.
Endogenous protective mechanisms against vasospasm exist, are powerful, and can be induced by PC. eNOS-derived nitric oxide is a critical mediator of PC-induced neurovascular protection. These data provide strong "proof-of-principle" evidence that PC represents a promising new strategy to reduce vasospasm and delayed cerebral ischemia after SAH.
血管痉挛导致的迟发性脑缺血仍然是蛛网膜下腔出血（SAH）患者发病率的主要原因。我们假设通过预处理（PC）激活先天神经血管保护机制可能是一种针对 SAH 诱导的血管痉挛和神经功能缺损的新治疗方法，其次，它提供的神经血管保护是由内皮型一氧化氮合酶（eNOS）介导的。
野生型小鼠接受缺氧预处理或常氧处理，24 小时后进行 SAH。每天分析神经功能；术后第 2 天评估血管痉挛。还评估了一氧化氮可用性、eNOS 表达和 eNOS 活性。在另一个实验中，野生型和 eNOS 缺失型小鼠接受缺氧预处理或常氧处理，然后进行 SAH，并评估血管痉挛和神经功能缺损。
PC 几乎完全预防了 SAH 诱导的血管痉挛和神经功能缺损。它还预防了 SAH 诱导的一氧化氮可用性降低和 eNOS 活性增加，无论是在有 SAH 还是没有 SAH 的小鼠中。野生型小鼠用一氧化氮合酶抑制剂 N(G)-硝基-L-精氨酸甲酯处理和 eNOS 缺失型小鼠中，PC 诱导的血管痉挛和神经功能缺损的保护作用丧失。
存在针对血管痉挛的内源性保护机制，它们很强大，可以通过 PC 诱导。eNOS 衍生的一氧化氮是 PC 诱导的神经血管保护的关键介质。这些数据提供了强有力的“原理证明”证据，表明 PC 是减少 SAH 后血管痉挛和迟发性脑缺血的一种很有前途的新策略。
