Sorafenib promotes sensory conduction function recovery via miR-142-3p/ AC9/cAMP axis post dorsal column injury
Sorafenib promotes sensory conduction function recovery via miR-142-3p/ AC9/cAMP axis post dorsal column injury
复制标题
索拉非尼通过背柱损伤后 miR-142-3p/AC9/cAMP 轴促进感觉传导功能恢复
DOI：
10.1016/j.neuropharm.2019.01.031
复制
发表时间：
2019-04-01
影响因子：
4.7
通讯作者：
Chen，Xueming
中科院分区：
文献类型：
--
作者：
Wang，Tianyi;Li，Bo;Chen，Xueming
脊髓损伤导致感觉功能障碍。本研究探讨了在坐骨神经条件性损伤（SNCI）中起关键作用的miR-142- 3 p促进背柱损伤修复的机制，并验证了其对初级感觉神经元（DRG）的作用。miR-142- 3 p表达在脊髓背柱损伤（SDCL）组中显著增加，在SNCI组中略有增加。随后，miR-142- 3 p的靶基因腺苷酸环化酶9（AC 9）的表达在SDCL组中急剧下降，而在SNCI组中下降有限。cAMP的表达趋势与miR-142- 3 p相反。MiR-142- 3 p抑制剂可延长轴突长度，上调AC 9、cAMP、p-CREB、IL-6和GAP 43的表达，下调GTP-RhoA的表达。miR-142- 3 p抑制剂联合AC 9 siRNA可缩短轴突长度，降低AC 9、cAMP、p-CREB、IL-6和GAP 43的表达，增加GTP-RhoA的表达。cAMP/PKA通路抑制剂H89和IL 6/STAT 3/GAP 43轴抑制剂AG 490可抑制miR-142- 3 p抑制剂对轴突生长的促进作用，并改变相应蛋白的表达水平。因此，研究了使用索拉非尼下调SNCI的miR-142- 3 p表达的替代疗法。结果显示，索拉非尼对体外轴突生长和体内感觉传导功能恢复的作用与miR-142- 3 p抑制剂和SNCI相似。总之，miR-142- 3 p在SNCI促进背柱损伤修复中起关键作用。索拉非尼通过下调miR-142- 3 p模拟SNCI的治疗效果，随后促进背柱损伤后感觉传导功能的恢复。
Spinal cord injury results in sensation dysfunction. This study explored miR-142-3p, which acts a critical role in sciatic nerve conditioning injury (SNCI) promoting the repair of the dorsal column injury and validated its function on primary sensory neuron(DRG). miR-142-3p expression increased greatly in the spinal cord dorsal column lesion (SDCL) group and increased slightly in the SNCI group. Subsequently, the expression of adenylate cyclase 9 (AC9), the target gene of miR-142-3p, declined sharply in the SDCL group and declined limitedly in the SNCI group. The expression trend of cAMP was opposite to that of miR-142-3p. MiR-142-3p inhibitor improved the axon length, upregulated the expression of AC9, cAMP, p-CREB, IL-6, and GAP43, and downregulated the expression of GTP-RhoA. miR-142-3p inhibitor combined with AC9 siRNA showed shorter axon length, the expression of AC9, cAMP, p-CREB, IL-6, and GAP43 was decreased, and the expression of GTP-RhoA was increased. H89 and AG490, inhibitors of cAMP/PKA pathway and IL6/STAT3/GAP43 axis, respectively, declined the enhanced axonal growth by miR-142-3p inhibitor and altered the expression level of the corresponding proteins. Thus, a substitution therapy using Sorafenib that downregulates the miR-142-3p expression for SNCI was investigated. The results showed the effect of Sorafenib was similar to that of miR-142-3p inhibitor and SNCI on both axon growth in vitro and sensory conduction function recovery in vivo. In conclusion, miR-142-3p acts a pivotal role in SNCI promoting the repair of dorsal column injury. Sorafenib mimics the treatment effect of SNCI via downregulation of miR-142-3p, subsequently, promoting sensory conduction function recovery post dorsal column injury.