Cyclotraxin-B, the first highly potent and selective TrkB inhibitor, has anxiolytic properties in mice.
Cyclotraxin-B, the first highly potent and selective TrkB inhibitor, has anxiolytic properties in mice.
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DOI：
10.1371/journal.pone.0009777
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发表时间：
2010-03-19
期刊：
影响因子：
3.7
通讯作者：
Prémont J
中科院分区：
文献类型：
--
作者：
Cazorla M;Jouvenceau A;Rose C;Guilloux JP;Pilon C;Dranovsky A;Prémont J
在过去的几十年里，很少有机械上的新型治疗剂被开发出来用于治疗精神和神经退行性疾病。大量研究表明，靶向BDNF及其TrkB受体可能是治疗脑部疾病的一种有前途的治疗策略。然而，为TrkB受体开发有效的小配体已被证明是困难的。通过模拟多肽的方法，我们开发了一种高效和选择性的TrkB抑制剂，环曲蛋白-B，能够改变TrkB依赖的分子和生理过程，如突触可塑性、神经元分化和BDNF诱导的神经毒性。环曲蛋白-B变构改变TrkB的构象，导致BDNF依赖和非依赖(基础)活性的抑制。最后，给小鼠全身给药后，小鼠大脑中的TrkB受到抑制，具有特定的抗焦虑类行为效应，而没有抗抑郁类活性。本研究表明，环曲蛋白B可能不仅是研究BDNF和TrkB在生理学和病理学中的作用的有力工具，而且也是开发治疗脑部疾病的新治疗策略的先导化合物。
In the last decades, few mechanistically novel therapeutic agents have been developed to treat mental and neurodegenerative disorders. Numerous studies suggest that targeting BDNF and its TrkB receptor could be a promising therapeutic strategy for the treatment of brain disorders. However, the development of potent small ligands for the TrkB receptor has proven to be difficult. By using a peptidomimetic approach, we developed a highly potent and selective TrkB inhibitor, cyclotraxin-B, capable of altering TrkB-dependent molecular and physiological processes such as synaptic plasticity, neuronal differentiation and BDNF-induced neurotoxicity. Cyclotraxin-B allosterically alters the conformation of TrkB, which leads to the inhibition of both BDNF-dependent and -independent (basal) activities. Finally, systemic administration of cyclotraxin-B to mice results in TrkB inhibition in the brain with specific anxiolytic-like behavioral effects and no antidepressant-like activity. This study demonstrates that cyclotraxin-B might not only be a powerful tool to investigate the role of BDNF and TrkB in physiology and pathology, but also represents a lead compound for the development of new therapeutic strategies to treat brain disorders.
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DOI：
10.1073/pnas.0709102105
发表时间：
2008-03-25
影响因子：
11.1
作者：
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