Department of Neurology, University of Mississippi Medical Center, Jackson, MS, USA; Institute of Clinical Medicine, University of Turku, Turku, Finland.
Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, MS, USA.
Eur J Pharmacol. 2018 Aug 15;833:531-544. doi: 10.1016/j.ejphar.2018.06.028. Epub 2018 Jun 20.
Ischemic stroke is a devastating and debilitating medical condition with limited therapeutic options. However, accumulating evidence indicates a central role of inflammation in all aspects of stroke including its initiation, the progression of injury, and recovery or wound healing. A central target of inflammation is disruption of the blood brain barrier or neurovascular unit. Here we discuss recent developments in identifying potential molecular targets and immunomodulatory approaches to preserve or protect barrier function and limit infarct damage and functional impairment. These include blocking harmful inflammatory signaling in endothelial cells, microglia/macrophages, or Th17/γδ T cells with biologics, third generation epoxyeicosatrienoic acid (EET) analogs with extended half-life, and miRNA antagomirs. Complementary beneficial pathways may be enhanced by miRNA mimetics or hyperbaric oxygenation. These immunomodulatory approaches could be used to greatly expand the therapeutic window for thrombolytic treatment with tissue plasminogen activator (t-PA). Moreover, nanoparticle technology allows for the selective targeting of endothelial cells for delivery of DNA/RNA oligonucleotides and neuroprotective drugs. In addition, although likely detrimental to the progression of ischemic stroke by inducing inflammation, oxidative stress, and neuronal cell death, 20-HETE may also reduce susceptibility of onset of ischemic stroke by maintaining autoregulation of cerebral blood flow. Although the interaction between inflammation and stroke is multifaceted, a better understanding of the mechanisms behind the pro-inflammatory state at all stages will hopefully help in developing novel immunomodulatory approaches to improve mortality and functional outcome of those inflicted with ischemic stroke.
缺血性中风是一种具有破坏性和使人虚弱的医疗状况，治疗选择有限。然而，越来越多的证据表明炎症在中风的各个方面都起着核心作用，包括其发作、损伤进展以及恢复或伤口愈合。炎症的一个核心靶点是破坏血脑屏障或神经血管单元。在这里，我们讨论了最近在确定潜在分子靶点和免疫调节方法方面的进展，这些方法可以保护或保护屏障功能，限制梗塞损伤和功能障碍。这些方法包括用生物制剂阻断内皮细胞、小胶质细胞/巨噬细胞或 Th17/γδ T 细胞中的有害炎症信号，用具有延长半衰期的第三代环氧二十碳三烯酸 (EET) 类似物，以及用 miRNA 拮抗剂。互补的有益途径可以通过 miRNA 模拟物或高压氧来增强。这些免疫调节方法可以极大地扩大组织型纤溶酶原激活剂 (t-PA) 溶栓治疗的治疗窗口。此外，纳米颗粒技术允许选择性地针对内皮细胞输送 DNA/RNA 寡核苷酸和神经保护药物。此外，尽管 20-HETE 通过诱导炎症、氧化应激和神经元细胞死亡而不利于缺血性中风的进展，但它也可能通过维持脑血流的自动调节来降低缺血性中风发作的易感性。尽管炎症与中风之间的相互作用是多方面的，但更好地了解炎症状态在各个阶段背后的机制有望有助于开发新的免疫调节方法，以提高缺血性中风患者的死亡率和功能预后。
