A new nerve growth factor-mimetic peptide active on neuropathic pain in rats
A new nerve growth factor-mimetic peptide active on neuropathic pain in rats
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DOI：
10.1523/jneurosci.5201-07.2008
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发表时间：
2008-03-12
影响因子：
5.3
通讯作者：
Martegani, Enzo
中科院分区：
文献类型：
--
作者：
Colangelo, Anna Maria;Bianco, Maria Rosaria;Martegani, Enzo
神经生长因子（NGF）-酪氨酸激酶受体A（TrkA）复合物的结构分析，定点诱变研究和氨基酸残基的化学修饰的结果已确定环1，环4，和N-末端区域的NGF分子作为最相关的其生物活性。我们合成了几种肽，模拟用适当的间隔区连接在一起的两个环（1和4），有或没有N-末端区域。命名为NL 1 L4和L1 L4的两种肽在低至3 μ M的浓度下表现出良好的NGF激动剂活性。它们诱导鸡背根神经节的分化并刺激TrkA受体的酪氨酸磷酸化，但不刺激TrkB受体。此外，L1 L4能够诱导PC 12细胞分化。更有趣的是，具有最高“体外”活性的肽（L1 L4）显示在外周神经性疼痛的大鼠模型中减少神经性行为并恢复神经元功能，从而表明这种NGF模拟肽的潜在治疗作用。
Analysis of the structure of nerve growth factor (NGF)-tyrosine kinase receptor A ( TrkA) complex, site-directed mutagenesis studies and results from chemical modification of amino acid residues have identified loop 1, loop 4, and the N-terminal region of the NGF molecule as the most relevant for its biological activity. We synthesized several peptides mimicking the two loops ( 1 and 4) linked together with an appropriate spacer, with or without the N-terminal region. Two peptides named NL1L4 and L1L4 demonstrated good NGF agonist activity at a concentration as low as 3 mu M. They induced differentiation of chick dorsal root ganglia and stimulated tyrosine phosphorylation of TrkA, but not TrkB, receptor. In addition L1L4 was able to induce differentiation of PC12 cells. More interestingly, the peptide with the highest "in vitro" activity (L1L4) was shown to reduce neuropathic behavior and restore neuronal function in a rat model of peripheral neuropathic pain, thereby suggesting a potential therapeutic role for this NGF-mimetic peptide.