Ahmed Zubair, Jacques Steven J, Berry Martin, Logan Ann
Molecular Neuroscience Group, School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Institute of Biomedical Research (West), Edgbaston, Birmingham B15 2TT, UK.
Neurobiol Dis. 2009 Oct;36(1):142-50. doi: 10.1016/j.nbd.2009.07.016. Epub 2009 Jul 24.
Administration of epidermal growth factor receptor (EGFR) inhibitors (e.g. AG1478/PD168393) promotes central nervous system (CNS) axon regeneration in vivo by an unknown mechanism. Here, we show that EGFR activation is not required for AG1478-/PD168393-induced neurite outgrowth in cultures of dorsal root ganglion neurons (DRGN) with added inhibitory CNS myelin extract (CME), but is mediated by the paracrine and autocrine actions of the glia-/neuron-derived neurotrophins (NT) NGF, BDNF and NT-3 through Trk signalling in DRGN potentiated by elevated cAMP levels. The DRGN neurite growth seen in CME-inhibited cultures treated with AG1478 is eradicated by blocking Trk signalling but undiminished after siRNA knockdown of >90% EGFR. Moreover, addition of the combined triplet of NT restores neurite outgrowth in CME-inhibited cultures, when cAMP levels are raised. Accordingly, we suggest that chemical EGFR inhibitors act independently of EGFR, inducing glia and neurons to secrete NT and raising cAMP levels in DRG cultures, leading to Trk-dependent disinhibited DRGN neurite outgrowth.
表皮生长因子受体（EGFR）抑制剂（如AG1478/PD168393）通过未知机制促进体内中枢神经系统（CNS）轴突再生。在此，我们表明，在添加抑制性中枢神经系统髓磷脂提取物（CME）的背根神经节神经元（DRGN）培养物中，AG1478-/PD168393诱导的神经突生长不需要EGFR激活，而是由神经胶质细胞/神经元衍生的神经营养因子（NT）NGF、BDNF和NT-3通过Trk信号传导的旁分泌和自分泌作用介导，cAMP水平升高可增强DRGN中的Trk信号传导。在用AG1478处理的CME抑制培养物中观察到的DRGN神经突生长通过阻断Trk信号传导而消除，但在EGFR的siRNA敲低>90%后并未减弱。此外，当cAMP水平升高时，添加三联体NT可恢复CME抑制培养物中的神经突生长。因此，我们认为化学EGFR抑制剂的作用独立于EGFR，诱导神经胶质细胞和神经元分泌NT并提高DRG培养物中的cAMP水平，导致Trk依赖性的DRGN神经突生长去抑制。
