Su Bin-Xiao, Chen Xin, Huo Jia, Guo Shu-Yun, Ma Rui, Liu Yan-Wu
Department of Anesthesiology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
Department of Anesthesiology, Shaanxi Provincial People's Hospital, Xi'an 710068, China.
Brain Res. 2017 Sep 15;1671:85-92. doi: 10.1016/j.brainres.2017.06.020. Epub 2017 Jul 14.
The essential role of GAPDH/Siah1 signaling pathway in the pathogenesis of various injurious conditions such as traumatic spinal cord injury (SCI) has been gradually recognized. However, the drugs targeting this signaling pathway are still lacking. The endocannabinoid system, including its receptors (CB1 and CB2), act as neuroprotective and immunomodulatory modulators in SCI. WIN55212-2, an agonist for CB1 and CB2 receptors, has been demonstrated with anti-inflammatory and anti-apoptotic effects in multiple neurological diseases. Therefore, the present study aimed to investigate whether WIN55212-2 could promote functional recovery after traumatic SCI via inhibition of the GAPDH/Siah1 signaling. The traumatic SCI was induced by dropping a 10-g impactor from 25mm on the dorsal surface of T9 and T10. Our results showed that WIN55212-2 alleviated the activation of GAPDH/Siah1 signaling pathway after SCI, as indicated by the reduction in GAPDH nuclear expression, GAPDH-Siah1 complex formation and iNOS protein expression. Furthermore, WIN55212-2 reduced apoptosis, production of IL-1β and TNF-α and activation of NF-κB signaling in the spinal cord after SCI. The behavioral tests showed that WIN55212-2 improved the functional recovery after traumatic SCI as indicated by sustained increase in the locomotor scores. However, these neuroprotective effects of WIN55212-2 were blocked in the presence of the combined treatment of AM630 (an antagonist of CB2) rather than AM251 (an antagonist of CB1). In conclusion, our study indicates that, WIN55212-2 improves the functional recovery after SCI via inhibition of GAPDH/Siah1 cascades in a CB2 receptor dependent manner, indicative of its therapeutic potential for traumatic SCI or other traumatic conditions.
GAPDH/Siah1信号通路在诸如创伤性脊髓损伤（SCI）等各种损伤性疾病发病机制中的重要作用已逐渐得到认可。然而，针对该信号通路的药物仍然缺乏。内源性大麻素系统，包括其受体（CB1和CB2），在SCI中发挥神经保护和免疫调节作用。WIN55212-2是CB1和CB2受体的激动剂，已在多种神经系统疾病中显示出抗炎和抗凋亡作用。因此，本研究旨在探讨WIN55212-2是否能通过抑制GAPDH/Siah1信号促进创伤性SCI后的功能恢复。通过从25毫米高度向下掉落一个10克的撞击器至T9和T10椎体背侧诱导创伤性SCI。我们的结果表明，WIN55212-2减轻了SCI后GAPDH/Siah1信号通路的激活，这表现为GAPDH核表达、GAPDH-Siah1复合物形成以及iNOS蛋白表达的减少。此外，WIN55212-2减少了SCI后脊髓中的细胞凋亡、IL-1β和TNF-α的产生以及NF-κB信号的激活。行为测试表明，WIN55212-2改善了创伤性SCI后的功能恢复，表现为运动评分持续增加。然而，WIN55212-2的这些神经保护作用在联合使用AM630（CB2拮抗剂）而非AM251（CB1拮抗剂）时被阻断。总之，我们的研究表明，WIN55212-2通过以CB2受体依赖性方式抑制GAPDH/Siah1级联反应来改善SCI后的功能恢复，这表明其对创伤性SCI或其他创伤性疾病具有治疗潜力。
