Department of Cell Biology, Emory University School of Medicine, Atlanta, Georgia, USA.
Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia, USA.
Eur J Neurosci. 2023 Sep;58(6):3555-3568. doi: 10.1111/ejn.16126. Epub 2023 Aug 22.
Limited axon regeneration following peripheral nerve injury may be related to activation of the lysosomal protease, asparaginyl endopeptidase (AEP, δ-secretase) and its degradation of the microtubule associated protein, Tau. Activity of AEP was increased at the site of sciatic nerve transection and repair but blocked in mice treated systemically with a specific AEP inhibitor, compound 11 (CP11). Treatments with CP11 enhanced axon regeneration in vivo. Amplitudes of compound muscle action potentials recorded 4 weeks after nerve transection and repair and 2 weeks after daily treatments with CP11 were double those of vehicle-treated mice. At that time after injury, axons of significantly more motor and sensory neurons had regenerated successfully and reinnervated the tibialis anterior and gastrocnemius muscles in CP11-treated mice than vehicle-treated controls. In cultured adult dorsal root ganglion neurons derived from wild type mice that were treated in vitro for 24 h with CP11, neurites were nearly 50% longer than in vehicle-treated controls and similar to neurite lengths in cultures treated with the TrkB agonist, 7,8-dihydroxyflavone (7,8-DHF). Combined treatment with CP11 and 7,8-DHF did not enhance outgrowth more than treatments with either one alone. Enhanced neurite outgrowth produced by CP11 was found also in the presence of the TrkB inhibitor, ANA-12, indicating that the enhancement was independent of TrkB signalling. Longer neurites were found after CP11 treatment in both TrkB+ and TrkB- neurons. Delta secretase inhibition by CP11 is a treatment for peripheral nerve injury with great potential.
周围神经损伤后轴突再生有限，可能与溶酶体蛋白酶天冬酰胺内肽酶（AEP，δ-分泌酶）的激活及其对微管相关蛋白 Tau 的降解有关。坐骨神经横断和修复部位 AEP 的活性增加，但在系统给予特异性 AEP 抑制剂 CP11 的小鼠中被阻断。CP11 的治疗增强了体内轴突再生。神经横断和修复后 4 周和 CP11 每日治疗 2 周后记录的复合肌肉动作电位幅度是载体处理小鼠的两倍。在损伤后那个时候，成功再生并重新支配 CP11 处理小鼠比载体处理对照小鼠的前胫骨肌和比目鱼肌的运动和感觉神经元的轴突数量明显更多。在体外用 CP11 处理 24 小时的野生型小鼠来源的培养成年背根神经节神经元中，神经突的长度比载体处理对照组长近 50%，与用 TrkB 激动剂 7,8-二羟基黄酮（7,8-DHF）处理的培养物中的神经突长度相似。CP11 与 7,8-DHF 的联合治疗并未增强比单独用任何一种治疗的生长更多。在存在 TrkB 抑制剂 ANA-12 的情况下也发现 CP11 产生的增强神经突生长，表明增强作用独立于 TrkB 信号传导。在用 CP11 处理后，在 TrkB+和 TrkB-神经元中都发现了更长的神经突。CP11 对 δ 分泌酶的抑制是治疗周围神经损伤的一种很有潜力的方法。
