English Arthur W, Carrasco Dario, Hoffman Dustin, Isaacson Robin, Kang Seong Su, Khan Samia, Liu Xia, Ye Keqiang
Department of Cell Biology, Emory University School of Medicine, Atlanta, GA, United States.
Rehabilitation Medicine, Emory University School of Medicine, Atlanta, GA, United States.
Front Cell Neurosci. 2022 Apr 15;16:857664. doi: 10.3389/fncel.2022.857664. eCollection 2022.
Axon regeneration after peripheral nerve injury is slow and inefficient, leading to generally poor functional recovery. Activity-dependent experimental therapies that increase expression of brain-derived neurotrophic factor (BDNF) and its TrkB receptors enhance regeneration, suggesting that treatments with BDNF might also be effective. However, recombinant human BDNF (rhBDNF), as well as 7,8-dihydroxyflavone (7,8-DHF), a small molecular BDNF mimetic, may have limited treatment applications because of their modest oral bioavailability and pharmacokinetic profile. R13 is a 7,8-DHF prodrug. Upon oral administration, it is converted in the liver to 7,8-DHF. In immunoblots from tissues at the site of nerve injury, a single oral treatment with R13 to mice following sciatic nerve transection and repair produced a rapid and prolonged increase in immunoreactivity to phosphorylated TrkB, prolonged phosphorylation of mitogen activated protein kinase (MAPK/Erk1/2), and a rapid but transient increase in phosphorylated AKT (protein kinase B). Intramuscular injections of fluorescent retrograde tracers into the gastrocnemius and tibialis anterior muscles 4 weeks after nerve injury resulted in significantly greater numbers of labeled motoneurons and dorsal root ganglion neurons in R13-treated mice than in vehicle-treated controls. Direct electromyographic (EMG) responses (M waves) were significantly larger in R13-treated mice 4 weeks after injury than vehicle-treated controls or mice treated with oral 7,8-DHF. Oral treatments with the prodrug, R13, are a potent therapy for stimulating axon regeneration and functional recovery after peripheral nerve injury.
外周神经损伤后轴突再生缓慢且效率低下，导致功能恢复普遍较差。增加脑源性神经营养因子（BDNF）及其TrkB受体表达的活动依赖性实验性疗法可促进再生，这表明用BDNF进行治疗可能也有效。然而，重组人BDNF（rhBDNF）以及小分子BDNF模拟物7,8-二羟基黄酮（7,8-DHF），由于其口服生物利用度和药代动力学特性有限，可能在治疗应用上受到限制。R13是一种7,8-DHF前药。口服后，它在肝脏中转化为7,8-DHF。在坐骨神经横断和修复后的小鼠神经损伤部位组织的免疫印迹中，对小鼠单次口服R13后，磷酸化TrkB的免疫反应性迅速且持续增加，丝裂原活化蛋白激酶（MAPK/Erk1/2）的磷酸化持续时间延长，磷酸化AKT（蛋白激酶B）迅速但短暂增加。神经损伤4周后，向腓肠肌和胫前肌内注射荧光逆行示踪剂，结果显示，与用赋形剂处理的对照组相比，R13处理的小鼠中标记的运动神经元和背根神经节神经元数量显著更多。损伤4周后，R13处理的小鼠的直接肌电图（EMG）反应（M波）明显大于赋形剂处理的对照组或口服7,8-DHF处理的小鼠。前药R13的口服治疗是一种有效的疗法，可促进外周神经损伤后的轴突再生和功能恢复。
