Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA.
Department of Pharmacology, A.T. Still University of Health Sciences, Kirksville College of Osteopathic Medicine, Kirksville, MO 63501, USA.
Exp Neurol. 2020 Dec;334:113484. doi: 10.1016/j.expneurol.2020.113484. Epub 2020 Oct 1.
Vasospasm and delayed cerebral ischemia (DCI) contribute significantly to the morbidity/mortality associated with aneurysmal subarachnoid hemorrhage (SAH). While considerable research effort has focused on preventing or reversing vasospasm, SAH-induced brain injury occurs in response to a multitude of concomitantly acting pathophysiologic mechanisms. In this regard, the pleiotropic epigenetic responses to conditioning-based therapeutics may provide an ideal SAH therapeutic strategy. We previously documented the ability of hypoxic preconditioning (PC) to attenuate vasospasm and neurological deficits after SAH, in a manner that depends on the activity of endothelial nitric oxide synthase. The present study was undertaken to elucidate whether the NAD-dependent protein deacetylase sirtuin isoform SIRT1 is an upstream mediator of hypoxic PC-induced protection, and to assess the efficacy of the SIRT1-activating polyphenol Resveratrol as a pharmacologic preconditioning therapy.
Wild-type C57BL/6J mice were utilized in the study and subjected to normoxia or hypoxic PC. Surgical procedures included induction of SAH via endovascular perforation or sham surgery. Multiple endpoints were assessed including cerebral vasospasm, neurobehavioral deficits, SIRT1 expression via quantitative real-time PCR for mRNA, and western blot for protein quantification. Pharmacological agents utilized in the study include EX-527 (SIRT1 inhibitor), and Resveratrol (SIRT1 activator).
Hypoxic PC leads to rapid and sustained increase in cerebral SIRT1 mRNA and protein expression. SIRT1 inhibition blocks the protective effects of hypoxic PC on vasospasm and neurological deficits. Resveratrol pretreatment dose-dependently abrogates vasospasm and attenuates neurological deficits following SAH - beneficial effects that were similarly blocked by pharmacologic inhibition of SIRT1.
SIRT1 mediates hypoxic preconditioning-induced protection against neurovascular dysfunction after SAH. Resveratrol mimics this neurovascular protection, at least in part, via SIRT1. Activation of SIRT1 is a promising, novel, pleiotropic therapeutic strategy to combat DCI after SAH.
血管痉挛和迟发性脑缺血（DCI）是与蛛网膜下腔出血（SAH）相关发病率和死亡率的主要原因。虽然大量研究致力于预防或逆转血管痉挛，但 SAH 引起的脑损伤是由多种同时作用的病理生理机制引起的。在这方面，条件治疗的多效性表观遗传反应可能提供一种理想的 SAH 治疗策略。我们之前记录了低氧预处理（PC）减轻 SAH 后血管痉挛和神经功能缺损的能力，这种能力依赖于内皮型一氧化氮合酶的活性。本研究旨在阐明 NAD 依赖性蛋白去乙酰化酶 SIRT1 同工型是否是低氧 PC 诱导保护的上游介质，并评估 SIRT1 激活多酚白藜芦醇作为药物预处理治疗的疗效。
本研究使用野生型 C57BL/6J 小鼠，并对其进行常氧或低氧 PC。手术程序包括通过血管内穿孔或假手术诱导 SAH。评估了多个终点，包括脑血管痉挛、神经行为缺陷、通过定量实时 PCR 评估 SIRT1 表达的 mRNA，以及 Western blot 评估蛋白质定量。本研究中使用的药物包括 EX-527（SIRT1 抑制剂）和白藜芦醇（SIRT1 激活剂）。
低氧 PC 导致大脑 SIRT1 mRNA 和蛋白质表达的快速和持续增加。SIRT1 抑制阻断低氧 PC 对血管痉挛和神经功能缺损的保护作用。白藜芦醇预处理剂量依赖性地消除 SAH 后的血管痉挛并减轻神经功能缺损-这种有益作用同样被 SIRT1 的药物抑制阻断。
SIRT1 介导低氧预处理诱导的 SAH 后神经血管功能障碍的保护作用。白藜芦醇至少部分通过 SIRT1 模拟这种神经血管保护作用。SIRT1 的激活是一种有前途的、新型的、多效性的治疗策略，可用于对抗 SAH 后的 DCI。
