PDF(Pubmed)
Abstract：
GRT-X, which targets both the mitochondrial translocator protein (TSPO) and the Kv7.2/3 (KCNQ2/3) potassium channels, has been shown to efficiently promote recovery from cervical spine injury. In the present work, we investigate the role of GRT-X and its two targets in the axonal growth of dorsal root ganglion (DRG) neurons. Neurite outgrowth was quantified in DRG explant cultures prepared from wild-type C57BL6/J and TSPO-KO mice. TSPO was pharmacologically targeted with the agonist XBD173 and the Kv7 channels with the activator ICA-27243 and the inhibitor XE991. GRT-X efficiently stimulated DRG axonal growth at 4 and 8 days after its single administration. XBD173 also promoted axonal elongation, but only after 8 days and its repeated administration. In contrast, both ICA27243 and XE991 tended to decrease axonal elongation. In dissociated DRG neuron/Schwann cell co-cultures, GRT-X upregulated the expression of genes associated with axonal growth and myelination. In the TSPO-KO DRG cultures, the stimulatory effect of GRT-X on axonal growth was completely lost. However, GRT-X and XBD173 activated neuronal and Schwann cell gene expression after TSPO knockout, indicating the presence of additional targets warranting further investigation. These findings uncover a key role of the dual mode of action of GRT-X in the axonal elongation of DRG neurons.
摘要：
GRT-X,靶向线粒体转运蛋白（TSPO）和Kv7.2/3（KCNQ2/3）钾通道，已被证明可以有效地促进颈椎损伤的恢复。在目前的工作中,我们研究了GRT-X及其两个靶点在背根神经节（DRG）神经元轴突生长中的作用。在由野生型C57BL6/J和TSPO-KO小鼠制备的DRG外植体培养物中定量神经突生长。TSPO在药理学上是用激动剂XBD173和用激活剂ICA-27243和抑制剂XE991靶向的Kv7通道。GRT-X在单次给药后4天和8天有效刺激DRG轴突生长。XBD173还促进轴突伸长，但仅在8天后及其重复给药。相比之下,ICA27243和XE991都倾向于降低轴突伸长率。在分离的DRG神经元/雪旺氏细胞共培养物中，GRT-X上调与轴突生长和髓鞘形成相关的基因的表达。在TSPO-KODRG文化中，GRT-X对轴突生长的刺激作用完全丧失。然而,GRT-X和XBD173激活TSPO敲除后神经元和雪旺细胞基因表达，表明存在需要进一步调查的其他目标。这些发现揭示了GRT-X双重作用模式在DRG神经元轴突伸长中的关键作用。
