Src family kinase inhibitor PP1 reduces secondary damage after spinal cord compression in rats
Src family kinase inhibitor PP1 reduces secondary damage after spinal cord compression in rats
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DOI：
10.1089/0897715041526230
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发表时间：
2004-07-01
影响因子：
4.2
通讯作者：
Yoshimine, T
中科院分区：
文献类型：
--
作者：
Akiyama, C;Yuguchi, T;Yoshimine, T
合成的pyrazolopy嘧啶，4-氨基-5-（4-甲基苯基）-7-（t-丁基）pyrazolo[3,4-d]嘧啶（PP1）是一种新型的、有效的、选择性的Src家族酪氨酸激酶抑制剂。血管通透性似乎是由血管内皮生长因子（VEGF）介导的，而VEGF需要激活下游Src家族激酶才能发挥其功能。本研究探讨了PP1对大鼠脊髓压迫模型血管通透性和炎症反应的影响。压缩10分钟后，给予PP1 （PP1组）或仅给药（对照组）。脊髓受压后第1、3、7天取出脊髓，进行组织病理学检查，检测VEGF表达及水肿、炎症程度。采用干重法测定脊髓含水量。压缩后6小时，采用实时聚合酶链反应（RT-PCR）系统检测与炎症反应相关的肿瘤坏死因子a （TNFalpha）和白细胞介素1 β (il -1 β) mRNA水平。虽然两组VEGF表达相似，但PP1组挫伤的程度在第3天减少了约35%。PP1组第1、3、7天的含水量显著降低，第3、7天的巨噬细胞浸润显著降低。PP1组TNFalpha和il -1 β mRNA的表达也显著降低。这些结果表明PP1减少了脊髓损伤后的继发性损伤。
The synthetic pyrazolopyrimidine, 4-amino-5-(4-methylphenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP1) is a novel, potent, and selective inhibitor of Src family tyrosine kinases. Vascular permeability appears to be mediated by vascular endothelial growth factor (VEGF), which requires the activation of downstream Src family kinases to exert its function. This study investigates the effects of PP1 on vascular permeability and inflammatory response in a rat spinal cord compression model. Ten minutes after compression, PP1 (PP1 group) or the vehicle only (control group) was administered. On days 1, 3, and 7 after compression, the spinal cords were removed and examined histopathologically to determine the expression of VEGF and the extent of edema and inflammation. The dry-weight method was used to measure the water content of the spinal cords. The mRNA levels of tumor necrosis factor a (TNFalpha) and interleukin 1beta (IL-1beta), which is related to inflammatory responses, were measured with a real-time polymerase chain reaction (RT-PCR) system 6 h after compression. Although VEGF expression was similar in both groups, the extent of contusional lesion in the PP1 group was reduced by approximately 35% on day 3. Moreover, the water content on days 1, 3, and 7 was significantly reduced and macrophage infiltration on days 3 and 7 was dramatically reduced in the PP1 group. TNFalpha and IL-1beta mRNA expression in the PP1 group were also significantly reduced. These results indicate that PP1 reduces secondary damage after spinal cord injury.