Department of Biomedical Sciences, University of Padua, Padua, Italy.
Padua Neuroscience Center, University of Padua, Padua, Italy.
Ann Clin Transl Neurol. 2019 Dec;6(12):2395-2402. doi: 10.1002/acn3.50926. Epub 2019 Nov 14.
To test whether the signaling axis CXCL12α-CXCR4 is activated upon crush/cut of the sciatic nerve and to test the activity of NUCC-390, a new CXCR4 agonist, in promoting nerve recovery from damage.
The sciatic nerve was either crushed or cut. Expression and localization of CXCL12α and CXCR4 were evaluated by imaging with specific antibodies. Their functional involvement in nerve regeneration was determined by antibody-neutralization of CXCL12α, and by the CXCR4 specific antagonist AMD3100, using as quantitative read-out the compound muscle action potential (CMAP). NUCC-390 activity on nerve regeneration was determined by imaging and CMAP recordings.
CXCR4 is expressed at the injury site within the axonal compartment, whilst its ligand CXCL12α is expressed in Schwann cells. The CXCL12α-CXCR4 axis is involved in the recovery of neurotransmission of the injured nerve. More importantly, the small molecule NUCC-390 is a strong promoter of the functional and anatomical recovery of the nerve, by acting very similarly to CXCL12α. This pharmacological action is due to the capability of NUCC-390 to foster elongation of motor neuron axons both in vitro and in vivo.
Imaging and electrophysiological data provide novel and compelling evidence that the CXCL12α-CXCR4 axis is involved in sciatic nerve repair after crush/cut. This makes NUCC-390 a strong candidate molecule to stimulate nerve repair by promoting axonal elongation. We propose this molecule to be tested in other models of neuronal damage, to lay the basis for clinical trials on the efficacy of NUCC-390 in peripheral nerve repair in humans.
检测挤压/切断坐骨神经后，CXCL12α-CXCR4 信号轴是否被激活，并检测新型 CXCR4 激动剂 NUCC-390 促进受损神经恢复的活性。
挤压/切断坐骨神经。用特异性抗体通过成像来评估 CXCL12α 和 CXCR4 的表达和定位。通过中和 CXCL12α 的抗体以及 CXCR4 特异性拮抗剂 AMD3100，确定其在神经再生中的功能作用，定量检测指标为复合肌肉动作电位（CMAP）。通过成像和 CMAP 记录来确定 NUCC-390 对神经再生的作用。
CXCR4 在损伤部位的轴突腔内表达，而其配体 CXCL12α 在施万细胞中表达。CXCL12α-CXCR4 轴参与了损伤神经的神经传递恢复。更重要的是，小分子 NUCC-390 通过与 CXCL12α 非常相似的作用，强烈促进神经的功能和解剖学恢复。这种药理作用归因于 NUCC-390 促进体外和体内运动神经元轴突伸长的能力。
成像和电生理数据提供了新的、令人信服的证据，表明 CXCL12α-CXCR4 轴参与了挤压/切断后的坐骨神经修复。这使得 NUCC-390 成为一种强有力的候选分子，通过促进轴突伸长来刺激神经修复。我们建议在其他神经元损伤模型中测试该分子，为 NUCC-390 在人类周围神经修复中的疗效临床试验奠定基础。
