A reliable method to reduce collagen scar formation in the lesioned rat spinal cord
A reliable method to reduce collagen scar formation in the lesioned rat spinal cord
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DOI：
10.1016/s0165-0270(01)00427-7
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发表时间：
2001-09-30
影响因子：
3
通讯作者：
Müller, HW
中科院分区：
文献类型：
--
作者：
Hermanns, S;Reiprich, P;Müller, HW
创伤性损伤后，胶质瘢痕的形成和细胞外基质（ECM）的沉积导致成年哺乳动物中枢神经系统（CNS）再生失败。使用后连合穹窿横断作为大鼠脑损伤模型，我们以前已经表明，在病变部位的胶原基底膜（BM）是轴突再生的主要障碍。通过给予铁螯合剂2，2 '-联吡啶（BPY）（脯氨酰4-羟化酶（PH）的抑制剂，胶原蛋白生物合成的关键酶），可以延迟该损伤模型中BM的沉积。为了研究这种潜在的治疗方法是否可以转移到其他CNS区域，我们选择了机械损伤的大鼠脊髓来研究BPY给药对BM形成的影响。由于病变区与脑膜成纤维细胞（一种分泌大量IV型胶原的细胞类型）非常接近，因此脊髓中的BM沉积比脑病变中广泛得多。无论是立即注射还是连续应用BPY，都不会导致脊髓中BM形成的可检测减少。只有抗瘢痕形成治疗的组合，包括（i）注射更有效的PH抑制剂[2，2 '-联吡啶]-5，5'-二羧酸（BPY-DCA），（ii）通过S-Br-cAMP选择性抑制成纤维细胞增殖和ECM产生，和（iii）连续应用BPY-DCA，显著减少了损伤诱导的BM。目前的结果清楚地表明，根据设计用于治疗脑损伤的方案单独应用BPY不足以减少损伤的成年大鼠脊髓中的BM形成。(C)2001 Elsevier Science B. V.保留所有权利。
Following traumatic injury, the formation of a glial scar and deposition of extracellular matrix (ECM) contributes to the regeneration failure in the adult mammalian central nervous system (CNS). Using a postcommissural fornix transection as a brain lesion model in rat, we have previously shown that the collagenous basement membrane (BM) at the lesion site is a major impediment for axon regeneration. Deposition of BM in this lesion model can be delayed by administration of the iron chelator 2,2'-bipyridine (BPY), an inhibitor of prolyl 4-hydroxylase (PH), a key enzyme of collagen biosynthesis. To examine whether this potential therapeutic approach is transferable to other CNS regions, we have chosen the mechanically lesioned rat spinal cord to investigate the effects of BPY administration on BM formation. Due to the close proximity of the lesion zone to meningeal fibroblasts, a cell-type secreting large amounts of collagen IV, BM deposition was much more extensive in the spinal cord than in the brain lesion. Neither immediate injections nor continuous application of BPY resulted in a detectable reduction of BM formation in the spinal cord. Only a combination of anti-scarring treatments including (i) injection of the more potent PH inhibitor [2,2'-bipyridine]-5,5'-dicarboxylic acid (BPY-DCA), (ii) selective inhibition of fibroblast proliferation and ECM production by S-Br-cAMP, and (iii) continuous application of BPY-DCA, reduced the lesion-induced BM significantly. The present results clearly demonstrate, that the exclusive application of BPY according to a protocol designed for treatment of brain lesions is not sufficient to reduce BM formation in the lesioned adult rat spinal cord. (C) 2001 Elsevier Science B.V. All rights reserved.