Department of Neurology, Center for Neural Development and Disease, The Interdepartmental Graduate Program in Neuroscience, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642, USA.
J Cereb Blood Flow Metab. 2011 Jun;31(6):1412-23. doi: 10.1038/jcbfm.2010.230. Epub 2011 Jan 19.
Prophylactic neuroprotection against stroke could reduce stroke burden in thousands of patients at high risk of stroke, including those with recent transient ischemic attacks (TIAs). Prolyl hydroxylase inhibitors (PHIs), such as deferoxamine (DFO), reduce stroke volume when administered at high doses in the peristroke period, which is largely mediated by the hypoxia-inducible transcription factor (HIF-1). Yet, in vitro experiments suggest that PHIs may also induce neuroprotection independent of HIF-1. In this study, we examine chronic, prophylactic, low-dose treatment with DFO, or another iron chelator deferasirox (DFR), to determine whether they are neuroprotective with this paradigm and mediate their effects through a HIF-1-dependent mechanism. In fact, prophylactic administration of low-dose DFO or DFR significantly reduces stroke volume. Surprisingly, DFO remained neuroprotective in mice haploinsufficient for HIF-1 (HIF-1+/-) and transgenic mice with conditional loss of HIF-1 function in neurons and astrocytes. Similarly, DFR was neuroprotective in HIF-1+/- mice. Neither DFO nor DFR induced expression of HIF-1 targets. Thus, low-dose chronic administration of DFO or DFR induced a prolonged neuroprotective state independent of HIF-1 function. As DFR is an orally administered and well-tolerated medication in clinical use, it has promise for prophylaxis against stroke in patients at high risk of stroke.
预防性神经保护可降低数千名高危卒中患者（包括近期短暂性脑缺血发作患者）的卒中负担。脯氨酰羟化酶抑制剂（PHI），如去铁胺（DFO），在卒中发生期高剂量给药时可减少卒中体积，主要通过缺氧诱导转录因子（HIF-1）介导。然而，体外实验表明，PHI 也可能通过不依赖于 HIF-1 的机制诱导神经保护。在这项研究中，我们研究了慢性、预防性、低剂量 DFO 或另一种铁螯合剂地拉罗司（DFR）治疗，以确定它们是否在此模型中具有神经保护作用，并通过 HIF-1 依赖的机制介导其作用。事实上，预防性给予低剂量 DFO 或 DFR 可显著降低卒中体积。令人惊讶的是，在 HIF-1 杂合不足（HIF-1+/-）的小鼠和神经元和星形胶质细胞中条件性丧失 HIF-1 功能的转基因小鼠中，DFO 仍具有神经保护作用。类似地，DFR 在 HIF-1+/-小鼠中也具有神经保护作用。DFO 和 DFR 均未诱导 HIF-1 靶基因的表达。因此，低剂量慢性给予 DFO 或 DFR 可诱导一种独立于 HIF-1 功能的持久神经保护状态。由于 DFR 是一种在临床上口服给药且耐受性良好的药物，因此有望用于预防高危卒中患者的卒中。
