Heme oxygenase-1-mediated neuroprotection in subarachnoid hemorrhage via intracerebroventricular deferoxamine.
Heme oxygenase-1-mediated neuroprotection in subarachnoid hemorrhage via intracerebroventricular deferoxamine.
复制标题
DOI：
10.1186/s12974-016-0709-1
复制
发表时间：
2016-09-13
影响因子：
9.3
通讯作者：
Hanafy KA
中科院分区：
文献类型：
--
作者：
LeBlanc RH 3rd;Chen R;Selim MH;Hanafy KA
蛛网膜下腔出血(SAH)是一种毁灭性的疾病，每年影响超过3万美国人。以前的动物研究已经探索了去铁胺(DFX)在SAH后的铁络合作用，但还没有人评估小胶质/巨噬细胞血红素加氧酶-1(HO-1或Hmox1)在DFX神经保护中的必要性，也没有人充分研究脑室(ICV)给药途径的有效性。我们探讨了全身和侧脑室注射DFX对SAH小鼠模型的治疗效果及其对小胶质/巨噬细胞HO-1的影响。将野生型(WT)小鼠分为4组：SAH假 + 治疗组、SAH + 治疗组、SAH + 腹膜腔内注射DFX组和SAH + 脑室注射DFX组。对每个实验组的神经元损伤、认知结果、血管痉挛、脑和血源性髓系细胞数量、脑IL-6浓度和线粒体超氧阴离子产生进行测量。用共聚焦图像检测HO-1与小胶质细胞的共定位。将WT或HO-1的−/−小胶质细胞和海马神经元分别用赋形剂、红血球或红细胞组进行处理，检测神经元损伤、肿瘤坏死因子-α浓度和小胶质细胞HO-1的表达。HO-1条件基因敲除用于研究髓系、神经元和星形胶质细胞HO-1在DFX诱导的神经保护和认知恢复中的作用。SAH后给予DFX治疗可减轻SAH后皮质损伤，改善SAH后认知结局，但对血管痉挛无影响；脑室DFX对神经保护作用最强。蛛网膜下腔出血后脑室注射DFX可降低脑内IL-6浓度，并有降低线粒体超氧阴离子生成的趋势。蛛网膜下腔出血后ICV DFX治疗增加了HO-1与小胶质细胞的共定位。DFX处理的WT小胶质细胞与跨孔内的红细胞相比，神经元损伤减少；这种作用在HO-1−/−小胶质细胞中被取消。蛛网膜下腔出血后侧脑室注射DFX可减少Hmox1fl/fl对照组和NesCre：Hmox1fl/fl小鼠的神经元损伤和改善认知功能，但不能降低LyzMCre：Hmox1fl/fl小鼠的认知功能。DFX的神经保护作用不依赖于血管痉挛。ICV DFX治疗在SAH小鼠模型中提供了卓越的神经保护作用。DFX对SAH后神经保护作用的机制可能与小胶质/巨噬细胞HO-1表达有关。在DFX治疗出血性中风期间监测患者HO-1的表达可能有助于临床医生识别更有可能对治疗有反应的患者。本文的在线版本(doi：10.1186/s12974-0160709-1)包含补充材料，授权用户可以使用。
Subarachnoid hemorrhage (SAH) is a devastating disease that affects over 30,000 Americans per year. Previous animal studies have explored the therapeutic effects of deferoxamine (DFX) via its iron-chelating properties after SAH, but none have assessed the necessity of microglial/macrophage heme oxygenase-1 (HO-1 or Hmox1) in DFX neuroprotection, nor has the efficacy of an intracerebroventricular (ICV) administration route been fully examined. We explored the therapeutic efficacy of systemic and ICV DFX in a SAH mouse model and its effect on microglial/macrophage HO-1. Wild-type (WT) mice were split into the following treatment groups: SAH sham + vehicle, SAH + vehicle, SAH + intraperitoneal (IP) DFX, and SAH + ICV DFX. For each experimental group, neuronal damage, cognitive outcome, vasospasm, cerebral and hematogenous myeloid cell populations, cerebral IL-6 concentration, and mitochondrial superoxide anion production were measured. HO-1 co-localization to microglia was measured using confocal images. Trans-wells with WT or HO-1−/− microglia and hippocampal neurons were treated with vehicle, red blood cells (RBCs), or RBCs with DFX; neuronal damage, TNF-α concentration, and microglial HO-1 expression were measured. HO-1 conditional knockouts were used to study myeloid, neuronal, and astrocyte HO-1 involvement in DFX-induced neuroprotection and cognitive recovery. DFX treatment after SAH decreased cortical damage and improved cognitive outcome after SAH yet had no effect on vasospasm; ICV DFX was most neuroprotective. ICV DFX treatment after SAH decreased cerebral IL-6 concentration and trended towards decreased mitochondrial superoxide anion production. ICV DFX treatment after SAH effected an increase in HO-1 co-localization to microglia. DFX treatment of WT microglia with RBCs in the trans-wells showed decreased neuronal damage; this effect was abolished in HO-1−/− microglia. ICV DFX after SAH decreased neuronal damage and improved cognition in Hmox1fl/fl control and NesCre:Hmox1fl/fl mice, but not LyzMCre:Hmox1fl/fl mice. DFX neuroprotection is independent of vasospasm. ICV DFX treatment provides superior neuroprotection in a mouse model of SAH. Mechanisms of DFX neuroprotection after SAH may involve microglial/macrophage HO-1 expression. Monitoring patient HO-1 expression during DFX treatment for hemorrhagic stroke may help clinicians identify patients that are more likely to respond to treatment. The online version of this article (doi:10.1186/s12974-016-0709-1) contains supplementary material, which is available to authorized users.
登录
查看更多内容
DOI：
10.1038/jcbfm.2010.137
发表时间：
2010-11
期刊：
Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism
影响因子：
--
作者：
通讯作者：
--
影响因子：
8.3
作者：
Okauchi M;Hua Y;Keep RF;Morgenstern LB;Schallert T;Xi G
通讯作者：
Xi G
影响因子：
4.1
作者：
Nakamura, T;Keep, RF;Xi, GH
通讯作者：
Xi, GH
影响因子：
6.3
作者：
Gao, Chao;Du, Hanjian;Xi, Guohua
通讯作者：
Xi, Guohua
影响因子：
158.5
作者：
ALLEN, GS;AHN, HS;TRANSOU, CR
通讯作者：
TRANSOU, CR