Small-molecule trkB agonists promote axon regeneration in cut peripheral nerves
Small-molecule trkB agonists promote axon regeneration in cut peripheral nerves
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DOI：
10.1073/pnas.1303646110
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发表时间：
2013-10-01
影响因子：
11.1
通讯作者：
Ye, Keqiang
中科院分区：
文献类型：
--
作者：
English, Arthur W.;Liu, Kevin;Ye, Keqiang
用两种小分子原肌球蛋白受体激酶B（trk B）配体、7，8二羟基黄酮（7，8 DHF）和脱氧盖杜宁治疗，评价它们促进小鼠损伤的外周神经中切割的轴突再生的能力，其中感觉和运动轴突被YFP标记。切割周围神经，用来自应变匹配、非荧光供体的移植物修复，并用纤维蛋白胶固定到位。2周后，从共聚焦图像测量再生YFP+轴突的轮廓。当纤维蛋白胶含有500 nM小分子trkB激动剂溶液稀释液时，轴突再生增强。在神经营养因子受体trkB在神经元中被选择性敲除的小鼠中，轴突再生非常弱，并且用7，8 DHF局部处理对轴突再生没有影响。用脱氧盖杜宁进行类似的治疗只有适度的效果。在有条件的BDNF基因敲除小鼠，局部治疗与7，8 DHF或deoxygedunin导致逆转不良的再生中发现的控制，并产生显着的增强再生。在每天腹膜内注射7，8 DHF或脱氧gedunin（5 mg/kg）2周的WT小鼠中，再生轴突轮廓几乎是对照组的两倍长。恢复坐骨神经刺激诱发的直接肌肉反应，在8周的生存期内，发现只有在治疗的小鼠预横断水平。用小分子trkB激动剂治疗增强了周围神经损伤后的轴突再生和肌肉神经再支配。
Treatments with two-small molecule tropomyosin receptor kinase B (trkB) ligands, 7,8 dihydroxyflavone (7,8 DHF) and deoxygedunin, were evaluated for their ability to promote the regeneration of cut axons in injured peripheral nerves in mice in which sensory and motor axons are marked by YFP. Peripheral nerves were cut and repaired with grafts from strain-matched, nonfluorescent donors and secured in place with fibrin glue. Lengths of profiles of regenerating YFP+ axons were measured 2 wk later from confocal images. Axon regeneration was enhanced when the fibrin glue contained dilutions of 500-nM solution of either small-molecule trkB agonist. In mice in which the neurotrophin receptor trkB is knocked out selectively in neurons, axon regeneration is very weak, and topical treatment with 7,8 DHF had no effect on axon regeneration. Similar treatments with deoxygedunin had only a modest effect. In conditional BDNF knockout mice, topical treatments with either 7,8 DHF or deoxygedunin resulted in a reversal of the poor regeneration found in controls and produced significant enhancement of regeneration. In WT mice treated with 2 wk of daily i.p. injections of either 7,8 DHF or deoxygedunin (5 mg/kg), regenerating axon profiles were nearly twice as long as in controls. Restoration of direct muscle responses evoked by sciatic nerve stimulation to pretransection levels over an 8-wk survival period was found only in the treated mice. Treatments with either small-molecule trkB agonist enhanced axon regeneration and muscle reinnervation after peripheral nerve injuries.