VEGF receptor antagonist Cyclo-VEGI reduces inflammatory reactivity and vascular leakiness and is neuroprotective against acute excitotoxic striatal insult.
VEGF receptor antagonist Cyclo-VEGI reduces inflammatory reactivity and vascular leakiness and is neuroprotective against acute excitotoxic striatal insult.
复制标题
DOI：
10.1186/1742-2094-5-18
复制
发表时间：
2008-05-20
影响因子：
9.3
通讯作者：
McLarnon JG
中科院分区：
文献类型：
--
作者：
Ryu JK;McLarnon JG
兴奋性脑损伤与广泛的神经元损伤有关，但也可能引起炎症反应和血管重塑。血管内皮生长因子（VEGF）抑制剂Cyclo-VEGI在纹状体内注射兴奋毒素喹啉酸（QUIN）后对VEGF表达、小胶质细胞增生和星形胶质细胞增生、血脑屏障（BBB）完整性和神经元活力的影响进行了研究。本研究的目的是研究VEGF依赖性炎症反应在兴奋性毒素注射脑和他们的依赖血管内皮生长因子受体的药理拮抗作用。细胞（小胶质细胞，星形胶质细胞，神经元）的反应和染料和蛋白质浸润的血脑屏障的单和双免疫荧光染色已被应用的情况下，和存在下，使用VEGF受体拮抗剂，环VEGI的药理学调节。使用Dunn-Bonferroni统计分析来测量动物组之间的显著性。在QUIN注射后1天的单个时间点的详细分析显示，与PBS注射相比，注射兴奋毒素的纹状体表现出小胶质细胞增生（ED 1标志物）、星形胶质细胞增生（GFAP标志物）和VEGF表达的显著增加。单一和双重免疫染色显示Cyclo-VEGI处理QUIN注射的纹状体对抑制小胶质细胞增生（38%）、ED 1/VEGF（42%）和VEGF纹状体免疫反应性（43%）具有显著作用;星形胶质细胞增生和GFAP/VEGF在Cyclo-VEGI处理下未发生显著改变。埃文斯蓝染料和血浆蛋白纤维蛋白原渗透到注射QUIN的纹状体中表明BBB出现渗漏，应用环VEGI后屏障渗透性恢复了62%（埃文斯蓝渗透性）和49%（纤维蛋白原渗透性）。QUIN诱导的毒性表现为纹状体神经元的损失（NeuN标记物）和神经元损伤的增加（Fluoro-Jade标记物），其中Cyclo-VEGI处理赋予显著的神经保护（NeuN增加33%，Fluoro-Jade减少38%）。VEGF受体介导的信号传导的拮抗剂Cyclo-VEGI已经显示出对纹状体兴奋性毒性损伤的广谱活性的功效，包括抑制小胶质细胞增生、减少BBB的渗漏和血浆纤维蛋白原的实质浸润，以及赋予纹状体神经元显著的保护。VEGF介导的活性的拮抗作用，可能针对反应性小胶质细胞上的VEGF受体，被认为是对抗炎症反应的神经保护机制和减轻急性兴奋性毒性损伤的新策略。
Excitotoxic brain insult is associated with extensive neuronal damage but could also cause inflammatory reactivity and vascular remodeling. The effects of the vascular endothelial growth factor (VEGF) inhibitor, Cyclo-VEGI on expression of VEGF, microgliosis and astrogliosis, blood-brain barrier (BBB) integrity and neuronal viability have been studied following intra-striatal injection of the excitotoxin, quinolinic acid (QUIN). The purpose of this study was to examine VEGF-dependent inflammatory responses in excitotoxin-injected brain and their dependence on pharmacological antagonism of VEGF receptors. Single and double immunofluorescence staining of cellular (microglia, astrocyte, neuron) responses and dye and protein infiltration of blood-brain barrier have been applied in the absence, and presence, of pharmacological modulation using a VEGF receptor antagonist, Cyclo-VEGI. Dunn-Bonferroni statistical analysis was used to measure for significance between animal groups. Detailed analysis, at a single time point of 1 d post-QUIN injection, showed excitotoxin-injected striatum to exhibit marked increases in microgliosis (ED1 marker), astrogliosis (GFAP marker) and VEGF expression, compared with PBS injection. Single and double immunostaining demonstrated significant effects of Cyclo-VEGI treatment of QUIN-injected striatum to inhibit microgliosis (by 38%), ED1/VEGF (by 42%) and VEGF striatal immunoreactivity (by 43%); astrogliosis and GFAP/VEGF were not significantly altered with Cyclo-VEGI treatment. Leakiness of BBB was indicated by infiltration of Evans blue dye and plasma protein fibrinogen into QUIN-injected striatum with barrier permeability restored by 62% (Evans blue permeability) and 49% (fibrinogen permeability) with Cyclo-VEGI application. QUIN-induced toxicity was demonstrated with loss of striatal neurons (NeuN marker) and increased neuronal damage (Fluoro-Jade marker) with significant neuroprotection conferred by Cyclo-VEGI treatment (33% increase in NeuN and 38% decrease in Fluoro-Jade). An antagonist for VEGF receptor-mediated signaling, Cyclo-VEGI, has shown efficacy in a broad spectrum of activity against striatal excitotoxic insult including inhibition of microgliosis, reduction in leakiness of BBB and parenchymal infiltration of plasma fibrinogen and in conferring significant protection for striatal neurons. Antagonism of VEGF-mediated activity, possibly targeting VEGF receptors on reactive microglia, is suggested as a neuroprotective mechanism against inflammatory reactivity and a novel strategy to attenuate acute excitotoxic damage.
登录
查看更多内容
影响因子：
5.3
作者：
Croll, SD;Ransohoff, RM;Wiegand, SJ
通讯作者：
Wiegand, SJ
影响因子：
5.3
作者：
Ryu, JK;Kim, SU;McLarnon, JG
通讯作者：
McLarnon, JG
DOI：
10.1093/jnen/61.10.914
发表时间：
2002-10-01
影响因子：
3.2
作者：
Proescholdt, MA;Jacobson, S;Merrill, MJ
通讯作者：
Merrill, MJ
影响因子：
2.9
作者：
Schmued, LC;Hopkins, KJ
通讯作者：
Hopkins, KJ
影响因子：
4.8
作者：
Dickstein, Dara L.;Biron, Kaan E.;Jefferies, Wilfred A.
通讯作者：
Jefferies, Wilfred A.