Erschbamer Matthias, Pernold Karin, Olson Lars
Department of Neuroscience, Karolinska Institutet, 171 77 Stockholm, Sweden.
J Neurosci. 2007 Jun 13;27(24):6428-35. doi: 10.1523/JNEUROSCI.1037-07.2007.
Lack of axon regeneration in the adult CNS has been attributed partly to myelin inhibitors and the properties of astrocytes. After spinal cord injury, proliferating astrocytes not only represent a physical barrier to regenerating axons but also express and secrete molecules that inhibit nerve growth, including chondroitin sulfate proteoglycans (CSPGs). Epidermal growth factor receptor (EGFR) activation triggers astrocytes into becoming reactive astrocytes, and EGFR ligands stimulate the secretion of CSPGs as well as the formation of cribriform astrocyte arrangements that contribute to the formation of glial scars. Recently, it was shown that EGFR inhibitors promote nerve regeneration in vitro and in vivo. Blocking a novel Nogo receptor interacting mechanism and/or effects of EGFR inhibition on astrocytes may underlie these effects. Here we show that rats subjected to weight-drop spinal cord injury can be effectively treated by direct delivery of a potent EGFR inhibitor to the injured area, leading to significantly better functional and structural outcome. Motor and sensory functions are improved and bladder function is restored. The robust effects and the fact that other EGFR inhibitors are in clinical use in cancer treatments make these drugs particularly attractive candidates for clinical trials in spinal cord injury.
成体中枢神经系统中轴突再生的缺乏部分归因于髓磷脂抑制剂和星形胶质细胞的特性。脊髓损伤后，增殖的星形胶质细胞不仅对再生轴突构成物理屏障，还表达和分泌抑制神经生长的分子，包括硫酸软骨素蛋白聚糖（CSPGs）。表皮生长因子受体（EGFR）激活会促使星形胶质细胞转变为反应性星形胶质细胞，EGFR配体可刺激CSPGs的分泌以及筛状星形胶质细胞排列的形成，而这种排列有助于胶质瘢痕的形成。最近的研究表明，EGFR抑制剂在体外和体内均能促进神经再生。阻断一种新的Nogo受体相互作用机制和/或EGFR抑制对星形胶质细胞的影响可能是这些作用的基础。在此，我们表明，通过将强效EGFR抑制剂直接递送至损伤部位，可有效治疗遭受重物坠落性脊髓损伤的大鼠，从而显著改善其功能和结构预后。运动和感觉功能得到改善，膀胱功能得以恢复。这些药物显著的治疗效果以及其他EGFR抑制剂正在用于癌症治疗的事实，使其成为脊髓损伤临床试验极具吸引力的候选药物。
