VAP-1 blockade prevents subarachnoid hemorrhage-associated cerebrovascular dilating dysfunction via repression of a neutrophil recruitment-related mechanism.
VAP-1 blockade prevents subarachnoid hemorrhage-associated cerebrovascular dilating dysfunction via repression of a neutrophil recruitment-related mechanism.
复制标题
VAP-1阻断通过抑制中性粒细胞募集相关机制来预防蛛网膜下腔出血相关的脑血管扩张功能障碍。
DOI：
10.1016/j.brainres.2015.01.047
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发表时间：
2015
期刊：
影响因子：
2.9
通讯作者：
Pelligrino,DaleA
中科院分区：
文献类型：
--
作者：
Xu,Haoliang;Testai,FernandoD;Valyi-Nagy,Tibor;NPavuluri,Mani;Zhai,Fengguo;Nanegrungsunk,Danop;Paisansathan,Chanannait;Pelligrino,DaleA
我们之前的研究结果表明，在蛛网膜下腔出血（SAH）的大鼠中，通过血管粘附蛋白-1（VAP-1）阻断来抑制SAH后神经炎症可以提供显着的神经保护作用。我们和其他人已经报道了神经炎症有助于脑微血管损伤。因此，在本研究中，我们测试了以下假设：（1）用LJP-1586（一种选择性VAP-1阻断剂）治疗，可预防SAH相关的软脑膜小动脉扩张功能障碍;（2）LJP-1586的血管保护作用源于抑制SAH诱导的中性粒细胞募集。我们使用了SAH的血管内穿孔模型。用LJP-1586治疗经历SAH的大鼠或通过抗中性粒细胞抗体治疗使其减少。将这些组的结果与各自的对照组进行比较。在SAH后48 h，评价大鼠的神经行为功能、软脑膜小静脉白细胞运输和软脑膜小动脉对局部应用的乙酰胆碱（ACh）和S-亚硝基-N-乙酰青霉胺（SNAP）的反应性。软脑膜小动脉反应在SAH后48小时降低。然而，在LJP-1586的存在下，这些应答被显著地保留。中性粒细胞耗竭产生了实质性抑制蛛网膜下腔出血相关的白细胞粘附和浸润。这是伴随着软脑膜小动脉扩张功能的显着保存，表明中性粒细胞募集和脑微血管反应性的损失之间的直接联系。此外，中性粒细胞耗竭还与神经行为功能的显著保护相关。目前的研究结果表明，减少蛛网膜下腔出血相关的中性粒细胞运输的升高将防止微血管功能障碍和随后的神经功能损害的发展。
Our previous findings indicated that in rats subjected to subarachnoid hemorrhage (SAH), suppression of post-SAH neuroinflammation via vascular adhesion protein-1 (VAP-1) blockade provides significant neuroprotection. We and others have reported that neuroinflammation contributes to cerebral microvascular impairment. Thus, in the present study, we tested the hypotheses that: (1) treatment with LJP-1586, a selective VAP-1 blocker, prevents SAH-associated pial arteriolar dilating dysfunction; and (2) the vasculoprotective effect of LJP-1586 arises from inhibiting SAH-elicited neutrophil recruitment. We utilized an endovascular perforation model of SAH. Rats subjected to SAH were either treated with LJP-1586 or rendered neutropenic via anti-neutrophil-antibody treatment. Findings from these groups were compared to their respective control groups. At 48 h post-SAH, rats were evaluated for neurobehavioral function, pial venular leukocyte trafficking, and pial arteriolar reactivity to topically-applied acetylcholine (ACh) andS-nitroso-N-acetyl penicillamine (SNAP). Pial arteriolar responses decreased at 48 h post-SAH. However, in the presence of LJP-1586, those responses were significantly preserved. Neutrophil-depletion yielded a substantial suppression of SAH-associated leukocyte adhesion and infiltration. This was accompanied by a significant preservation of pial arteriolar dilating function, suggesting a direct link between neutrophil recruitment and the loss of cerebral microvascular reactivity. Moreover, neutrophil depletion also was associated with significant protection of neurobehavioral function. The present findings suggest that attenuating SAH-linked elevation in neutrophil trafficking will protect against the development of microvascular dysfunction and subsequent neurological impairment.