Oral Treatments With the TrkB Ligand Prodrug, R13, Promote Enhanced Axon Regeneration Following Peripheral Nerve Injury.
Oral Treatments With the TrkB Ligand Prodrug, R13, Promote Enhanced Axon Regeneration Following Peripheral Nerve Injury.
复制标题
DOI：
10.3389/fncel.2022.857664
复制
发表时间：
2022
影响因子：
5.3
通讯作者：
Ye, Keqiang
中科院分区：
文献类型：
--
作者：
English, Arthur W.;Carrasco, Dario;Hoffman, Dustin;Isaacson, Robin;Kang, Seong Su;Khan, Samia;Liu, Xia;Ye, Keqiang
关键词：
周围神经损伤后的轴突再生缓慢且效率低下，导致功能恢复通常较差。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疗法可增强再生，这表明BDNF治疗也可能有效。然而，重组人BDNF（rhBDNF），以及7，8-二羟基黄酮（7，8-DHF），一种小分子BDNF模拟物，可能有有限的治疗应用，因为它们适度的口服生物利用度和药代动力学特征。R13是7，8-DHF前药。口服给药后，它在肝脏中转化为7，8-DHF。在神经损伤部位组织的免疫印迹中，对坐骨神经切断和修复后的小鼠进行R13单次口服治疗，导致对磷酸化Trk B的免疫反应性快速且持续增加，有丝分裂原活化蛋白激酶（MAPK/Erk 1/2）的磷酸化延长，磷酸化AKT（蛋白激酶B）快速但短暂增加。肌内注射荧光逆行示踪剂到腓肠肌和胫骨前肌神经损伤后4周导致标记的运动神经元和背根神经节神经元的R13治疗的小鼠比在车辆治疗的对照组显着更大的数量。直接肌电图（EMG）反应（M波）在R13治疗的小鼠损伤后4周明显大于溶剂治疗的对照组或口服7，8-DHF治疗的小鼠。口服前体药物R13是刺激周围神经损伤后轴突再生和功能恢复的有效疗法。
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.
登录
查看更多内容
影响因子：
3.7
作者：
Jang SW;Liu X;Chan CB;France SA;Sayeed I;Tang W;Lin X;Xiao G;Andero R;Chang Q;Ressler KJ;Ye K
通讯作者：
Ye K
影响因子：
2.2
作者：
English, Arthur W.;Wilhelm, Jennifer C.;Sabatier, Manning J.
通讯作者：
Sabatier, Manning J.
DOI：
10.1523/jneurosci.1411-11.2012
发表时间：
2012-04-04
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Wilhelm JC;Xu M;Cucoranu D;Chmielewski S;Holmes T;Lau KS;Bassell GJ;English AW
通讯作者：
English AW
影响因子：
6.1
作者：
Wurzelmann M;Romeika J;Sun D
通讯作者：
Sun D
影响因子：
3.4
作者：
McGregor, Claire;Sabatier, Manning;English, Arthur
通讯作者：
English, Arthur