Amphotericin B, identified from a natural product screen, antagonizes CNS inhibitors to promote axon growth via activation of an Akt pathway in neurons
Amphotericin B, identified from a natural product screen, antagonizes CNS inhibitors to promote axon growth via activation of an Akt pathway in neurons
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DOI：
10.1111/j.1471-4159.2010.06704.x
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发表时间：
2010-06-01
影响因子：
4.7
通讯作者：
Walsh, Frank S.
中科院分区：
文献类型：
--
作者：
Gao, Ying;Deng, Kangwen;Walsh, Frank S.
成年中枢神经系统轴突再生的主要障碍之一是髓鞘和胶质瘢痕产生的抑制分子。到目前为止，只有少数药理学化合物在促进损伤后轴突再生方面表现出对抗CNS抑制剂的功能活性。为了寻找新的化合物，促进神经突生长在体外，我们开始了一个筛选的天然产物的集合。我们确定了四种具有促进髓鞘基质生长潜力的化合物。其中，两性霉素B（Amphotericin B，AmB）被证明可以增强神经突生长并拮抗主要髓鞘相关抑制剂和神经胶质疤痕衍生的硫酸软骨素蛋白聚糖的活性。发现AmB激活Akt，从而抑制糖原合成酶激酶3 β的活性。此外，抑制Akt活性的细胞渗透性肽显示阻断AmB促进轴突生长的作用，而另一种增加Akt活性的肽在髓鞘相关抑制剂存在下刺激轴突生长。我们的研究结果表明，AmB可以通过激活Akt的机制，在广泛的抑制底物促进神经突生长。
P>One of the major barriers to successful axon regeneration in the adult CNS is the presence of inhibitory molecules that originate from the myelin sheath and glial scar. So far, only a small number of pharmacological compounds have exhibited functional activity against CNS inhibitors in promoting axon regeneration after injury. To search for novel compounds that enhance neurite outgrowth in vitro, we initiated a screen of a collection of natural products. We identified four compounds with the potential to promote growth over a myelin substrate. Of these, Amphotericin B (AmB) was shown to enhance neurite outgrowth and antagonize activities of major myelin associated inhibitors and glial-scar-derived chondroitin sulfate proteoglycans. AmB was found to activate Akt and thereby suppress the activity of glycogen synthase kinase 3 beta. Also, a cell permeable peptide that inhibits Akt activity was shown to block the effect of AmB in promoting axonal growth, while another peptide that increases Akt activity stimulated axonal growth in the presence of the myelin associated inhibitors. Our results suggest that AmB can promote neurite outgrowth over a wide range of inhibitory substrates via a mechanism that involves activation of Akt.