Suppression of astroglial scar formation and enhanced axonal regeneration associated with functional recovery in a spinal cord injury rat model by the cell cycle inhibitor olomoucine
Suppression of astroglial scar formation and enhanced axonal regeneration associated with functional recovery in a spinal cord injury rat model by the cell cycle inhibitor olomoucine
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DOI：
10.1002/jnr.20999
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发表时间：
2006-10
影响因子：
4.2
通讯作者：
Daishi Tian;Zhi-yuan Yu;M. Xie;B. Bu;Otto W. Witte;Wei Wang
中科院分区：
文献类型：
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作者：
Daishi Tian;Zhi-yuan Yu;M. Xie;B. Bu;Otto W. Witte;Wei Wang
众所周知，成年哺乳动物中枢神经系统的轴突在受伤后只能再生有限的数量。星形胶质细胞被认为在再生失败中起关键作用，产生多种抑制性蛋白聚糖，如硫酸软骨素蛋白聚糖（CSPG）。脊髓损伤后，星形胶质细胞肥大增殖，在损伤部位形成密集的星形胶质细胞突起网络，构成物理和生化屏障。下调星形胶质细胞增殖和抑制CSPG产生可能促进轴突再生。最近的研究表明，细胞周期机制的异常激活导致细胞在各种损伤中过度增殖和凋亡。在本研究中，我们试图确定细胞周期抑制剂，olomoucine，是否会减少神经元细胞死亡，限制星形胶质细胞增殖和抑制性CSPGs的产生，并最终增强SCI后大鼠的功能补偿。我们的研究结果表明，细胞周期组分的上调与SCI后神经元细胞死亡和星形胶质细胞增殖以及CSPGs的产生密切相关。同时，给予选择性细胞周期激酶（CDK）抑制剂奥洛莫辛（olomoucine）显著降低了上调的细胞周期蛋白，从而减少了神经元细胞死亡、星形胶质细胞增殖和CSPG的积累。更重要的是，使用奥洛莫辛治疗还增加了生长相关蛋白-43的表达，减少了空洞形成，并改善了功能缺陷。我们认为抑制急性SCI星形胶质细胞周期有利于轴突生长。在未来，治疗策略可以设计，以实现有效的轴突再生和功能补偿创伤性中枢神经系统损伤后。© 2006 Wiley利斯公司
It is well established that axons of the adult mammalian CNS are capable of regrowing only a limited amount after injury. Astrocytes are believed to play a crucial role in the failure to regenerate, producing multiple inhibitory proteoglycans, such as chondroitin sulphate proteoglycans (CSPGs). After spinal cord injury (SCI), astrocytes become hypertrophic and proliferative and form a dense network of astroglial processes at the site of lesion constituting a physical and biochemical barrier. Down‐regulations of astroglial proliferation and inhibitory CSPG production might facilitate axonal regeneration. Recent reports indicated that aberrant activation of cell cycle machinery contributed to overproliferation and apoptosis of cells in various insults. In the present study, we sought to determine whether a cell cycle inhibitior, olomoucine, would decrease neuronal cell death, limit astroglial proliferation and production of inhibitory CSPGs, and eventually enhance the functional compensation after SCI in rats. Our results showed that up‐regulations of cell cycle components were closely associated with neuronal cell death and astroglial proliferation as well as the production of CSPGs after SCI. Meanwhile, administration of olomoucine, a selective cell cycle kinase (CDK) inhibitor, has remarkably reduced the up‐regulated cell cycle proteins and then decreased neuronal cell death, astroglial proliferation, and accumulation of CSPGs. More importantly, the treatment with olomoucine has also increased expression of growth‐associated proteins‐43, reduced cavity formation, and improved functional deficits. We consider that suppressing astroglial cell cycle in acute SCIs is beneficial to axonal growth. In the future, therapeutic strategies can be designed to achieve efficient axonal regeneration and functional compensation after traumatic CNS injury. © 2006 Wiley‐Liss, Inc.