Peripheral nerve regeneration following injury is altered in mice lacking P2X7 receptor,European Journal of Neuroscience

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Peripheral nerve regeneration following injury is altered in mice lacking P2X7 receptor
European Journal of Neuroscience ( IF 2.7 ) Pub Date : 2020-10-04 , DOI: 10.1111/ejn.14995
Valerio Magnaghi ₁ , Sarah Martin ₂ , Patrick Smith ₂ , Luke Allen ₂ , Vincenzo Conte ₃ , Adam J Reid _{2,

4} , Alessandro Faroni ₂

Affiliation

Peripheral nerve injuries are debilitating, and current clinical management is limited to surgical intervention, which often leads to poor functional outcomes. Development of pharmacological interventions aimed at enhancing regeneration may improve this. One potential pharmacological target is the P2X purinergic receptor 7 (P2X7R) expressed in Schwann cells, which is known to play a role during the development of the peripheral nerves. Herein, we analysed differences in regeneration between genetically engineered P2X7 knockout mice and wild-type controls, using in vivo and ex vivo models of peripheral nerve regeneration. We have found that the speed of axonal regeneration is unaltered in P2X7 knockout mice, nevertheless regenerated P2X7 knockout nerves are morphologically different to wild-type nerves following transection and immediate repair. Indeed, the detailed morphometric analysis at 4 and 8 weeks after injury showed evidence of delayed remyelination in P2X7 knockout mice, compared to the wild-type controls. Furthermore, the Wallerian degeneration phase was unaltered between the two experimental groups. We also analysed gene expression changes in the dorsal root ganglia neurones as a result of the peripheral nerve injury, and found changes in pathways related to pain, inflammation and cell death. We conclude that P2X7 receptors in Schwann cells may be a putative pharmacological target to control cell fate following injury, thus enhancing nerve re-myelination.

中文翻译：

缺乏 P2X7 受体的小鼠损伤后周围神经再生发生改变

周围神经损伤使人衰弱，目前的临床管理仅限于手术干预，这通常会导致较差的功能结果。开发旨在促进再生的药物干预措施可能会改善这一点。一个潜在的药理学靶点是在雪旺细胞中表达的 P2X 嘌呤受体 7 (P2X7R)，已知其在周围神经的发育过程中发挥作用。在这里，我们使用周围神经再生的体内和离体模型分析了基因工程 P2X7 敲除小鼠和野生型对照之间的再生差异。我们发现在 P2X7 敲除小鼠中轴突再生的速度没有改变，但是在横断和立即修复后，再生的 P2X7 敲除神经在形态上与野生型神经不同。事实上，与野生型对照相比，损伤后 4 周和 8 周的详细形态分析显示 P2X7 敲除小鼠的髓鞘再生延迟。此外，两个实验组之间的沃勒变性阶段没有改变。我们还分析了由于周围神经损伤导致的背根神经节神经元的基因表达变化，并发现了与疼痛、炎症和细胞死亡相关的通路的变化。我们得出结论，雪旺细胞中的 P2X7 受体可能是控制损伤后细胞命运的推定药理学靶点，从而增强神经髓鞘再生。两个实验组之间的沃勒变性阶段没有改变。我们还分析了由于周围神经损伤导致的背根神经节神经元的基因表达变化，并发现了与疼痛、炎症和细胞死亡相关的通路的变化。我们得出结论，雪旺细胞中的 P2X7 受体可能是控制损伤后细胞命运的推定药理学靶点，从而增强神经髓鞘再生。两个实验组之间的沃勒变性阶段没有改变。我们还分析了由于周围神经损伤导致的背根神经节神经元的基因表达变化，并发现了与疼痛、炎症和细胞死亡相关的通路的变化。我们得出结论，雪旺细胞中的 P2X7 受体可能是控制损伤后细胞命运的推定药理学靶点，从而增强神经髓鞘再生。

更新日期：2020-10-04

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