Treatments with the specific δ-secretase inhibitor, compound 11, promote the regeneration of motor and sensory axons after peripheral nerve injury
Treatments with the specific δ-secretase inhibitor, compound 11, promote the regeneration of motor and sensory axons after peripheral nerve injury
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DOI：
10.1111/ejn.16126
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发表时间：
2023-08-22
影响因子：
3.4
通讯作者：
English, Arthur W. W.
中科院分区：
文献类型：
--
作者：
Isaacson, Robin H. H.;Carrasco, Dario I. I.;English, Arthur W. W.
周围神经损伤后轴突再生受限可能与溶酶体蛋白水解酶、天冬酰胺内肽酶(AEP)的激活及其对微管相关蛋白Tau的降解有关。在小鼠坐骨神经切断和修复部位，AEP的活性增加，而用AEP特异性抑制剂化合物11(CP11)系统治疗的小鼠，AEP活性被阻断。CP11处理可促进体内轴突再生。复合肌肉动作电位的波幅在神经切断和修复后4周和CP11每日治疗后2周是赋形剂治疗组的两倍。在损伤后，CP11处理组小鼠的运动神经元和感觉神经元的轴突成功再生并重新支配胫前肌和腓肠肌，明显多于赋形剂处理的对照组。体外培养的成年野生型小鼠背根神经节神经元经CP11处理24 h后，突起长度较溶剂对照组延长近50%，与TrkB激动剂7，8-二羟基黄酮(7，8-DHF)处理组的突起长度相近。CP11和7，8-DHF的联合处理对生长发育的促进作用并不比单独使用任何一种处理更大。在TrkB抑制剂ANA-12存在下，也发现CP11产生的突起生长增强，表明这种增强不依赖于TrkB信号转导。CP11处理后，TrkB+和TrkB-神经元的突起均变长。CP11抑制Delta分泌酶是治疗周围神经损伤的一种很有潜力的方法。
Limited axon regeneration following peripheral nerve injury may be related to activation of the lysosomal protease, asparaginyl endopeptidase (AEP, delta-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.