Inhibition of Src phosphorylation reduces damage to the blood-brain barrier following transient focal cerebral ischemia in rats.
Inhibition of Src phosphorylation reduces damage to the blood-brain barrier following transient focal cerebral ischemia in rats.
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抑制 Src 磷酸化可减少大鼠短暂局灶性脑缺血后血脑屏障的损伤。
DOI：
10.3892/ijmm.2014.1946
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发表时间：
2014-12
影响因子：
5.4
通讯作者：
Qin X
中科院分区：
文献类型：
--
作者：
Bai Y;Xu G;Xu M;Li Q;Qin X
脑缺血引起的血脑屏障（BBB）破坏决定了损伤的程度和患者的预后。Src抑制剂可以显著减小梗死面积并保持神经功能。Src蛋白酪氨酸激酶（PTK）抑制剂PP2可能通过降低血管内皮生长因子A （VEGFA）表达和上调cludin -5表达来保护大鼠脑免受缺血性损伤，从而保持血脑屏障的完整性。本研究通过测定磷酸化(p)-Src、VEGFA和claudin-5的表达水平，研究这些蛋白水平的变化，并确定脑缺血/再灌注（I/R）后PP2治疗的益处。我们的研究包括假手术组、I/R组、载体处理组(V)和PP2处理组（PP2）。我们发现，与I/R和V组相比，PP2组大鼠表现出更大的神经功能保存，VEGFA和p-Src蛋白表达降低。再灌注3 d后，PP2组claudin-5 mRNA和蛋白水平明显高于I/R组和V组。免疫荧光染色显示，PP2组纤维蛋白原和claudin-5的共定位免疫染色减少，说明PP2组纤维蛋白原的渗出量少于I/R和V组。此外，神经胶质纤维酸性蛋白（GFAP）和claudin-5的免疫染色共定位降低，表明PP2组大鼠的血脑屏障只有轻微的破坏。这些发现表明，PP2治疗可以减轻缺血后血脑屏障的破坏，并将神经功能缺陷降至最低；这些影响与VEGFA表达减少和claudin-5表达增加有关。Src PTK家族成员可能是脑缺血后血脑屏障保护的关键靶点。
The disruption of the blood-brain barrier (BBB) caused by cerebral ischemia determines the extent of injury and patient prognosis. Inhibitors of Src can markedly minimize the infarct size and preserve neurological function. The Src protein tyrosine kinase (PTK) inhibitor, PP2, protects the rat brain against ischemic injury, possibly through the reduction of vascular endothelial growth factor A (VEGFA) expression and the upregulation of claudin-5 expression, which preserves the integrity of the BBB. In this study, the expression levels of phosphorylated (p)-Src, VEGFA and claudin-5 were determined to investigate the changes occurring in the levels of these proteins and to determine the benefits of PP2 treatment following cerebral ischemia/reperfusion (I/R). Our study included a sham-operated group, an I/R group, a vehicle-treated group (V) and a PP2-treated group (PP2). We found that the rats in the PP2 group exhibited greater preservation of neurological function and reduced VEGFA and p-Src protein expression compared with the rats in the I/R and V groups. Moreover, the mRNA and protein levels of claudin-5 were markedly higher in the PP2 group than in the I/R group or the V group after 3 days of reperfusion. Immunofluorescence staining revealed that the co-localized immunostaining of fibrinogen and claudin-5 was reduced in the PP2 group, which suggests that the exudation of fibrinogen in this group was less than that in the I/R and V groups. Furthermore, the reduced co-localization of immunostaining of glial fibrillary acidic protein (GFAP) and claudin-5 indicated that the rats in the PP2 group had only a slight disruption of the BBB. These findings suggested that PP2 treatment attenuated the disruption of the BBB following ischemia and minimized the neurological deficit; these effects were associated with a decreased VEGFA expression and an increased claudin-5 expression. Members of the Src PTK family may be critical targets for the protection of the BBB following cerebral ischemia.
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影响因子：
11.2
作者：
Liu, Da-Zhi;Ander, Bradley P.;Xu, Huichun;Shen, Yan;Kaur, Pali;Deng, Wenbin;Sharp, Frank R.
通讯作者：
Sharp, Frank R.
DOI：
10.1083/jcb.147.1.185
发表时间：
1999-10-04
期刊：
The Journal of cell biology
影响因子：
--
作者：
Morita K;Sasaki H;Furuse M;Tsukita S
通讯作者：
Tsukita S
DOI：
10.1073/pnas.0808698106
发表时间：
2009-02-10
影响因子：
11.1
作者：
Argaw, Azeb Tadesse;Gurfein, Blake T.;John, Gareth R.
通讯作者：
John, Gareth R.
影响因子：
12.7
作者：
Nag, Sukriti;Venugopalan, Roopa;Stewart, Duncan J.
通讯作者：
Stewart, Duncan J.
影响因子：
3.5
作者：
Lennmyr, F;Ericsson, A;Terént, A
通讯作者：
Terént, A