Compounds co-targeting kinases in axon regulatory pathways promote regeneration and behavioral recovery after spinal cord injury in mice.
Compounds co-targeting kinases in axon regulatory pathways promote regeneration and behavioral recovery after spinal cord injury in mice.
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DOI：
10.1016/j.expneurol.2022.114117
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发表时间：
2022-09
影响因子：
5.3
通讯作者：
Bixby, John L.
中科院分区：
文献类型：
--
作者：
Mah, Kar Men;Wu, Wei;Al-Ali, Hassan;Sun, Yan;Han, Qi;Ding, Ying;Munoz, Melissa;Xu, Xiao-Ming;Lemmon, Vance P.;Bixby, John L.
关键词：
脊髓损伤 (SCI) 和其他中枢神经系统 (CNS) 创伤的恢复因 CNS 轴突再生的限制而受到阻碍。再生受到神经元固有再生能力缺乏和受损轴突所面临的抑制性微环境的限制。为了应对这一挑战，我们开发了一种治疗策略，共同靶向参与外在和内在调节途径的激酶。先前的工作发现了一种具有有利的多药理学（共同抑制 ROCK2 和 S6K1 等靶标）的激酶抑制剂 (RO48)，可促进体外中枢神经系统轴突生长和小鼠锥体切开模型中皮质脊髓束 (CST) 的萌芽。我们现在表明，RO48 在体外促进感觉神经元和各种中枢神经系统神经元的神经突生长，并在多种脊髓损伤小鼠模型中促进 CST 萌芽和/或再生。值得注意的是，RO48 的这些体内效应可以在不同实验室不同时间进行的几个独立实验系列中观察到。最后，在颈背半切模型中，RO48 不仅促进了病灶外 CST 轴突的生长，而且还改善了旋转棒、网格行走和颗粒回收任务中的行为恢复。我们的结果为 RO48 作为促进轴突生长和再生的有效化合物提供了有力的证据。此外，他们还指出了提高临床前模型干预稳健性的策略。
Recovery from spinal cord injury (SCI) and other central nervous system (CNS) trauma is hampered by limits on axonal regeneration in the CNS. Regeneration is restricted by the lack of neuron-intrinsic regenerative capacity and by the repressive microenvironment confronting damaged axons. To address this challenge, we have developed a therapeutic strategy that co-targets kinases involved in both extrinsic and intrinsic regulatory pathways. Prior work identified a kinase inhibitor (RO48) with advantageous polypharmacology (co-inhibition of targets including ROCK2 and S6K1), which promoted CNS axon growth in vitro and corticospinal tract (CST) sprouting in a mouse pyramidotomy model. We now show that RO48 promotes neurite growth from sensory neurons and a variety of CNS neurons in vitro, and promotes CST sprouting and/or regeneration in multiple mouse models of spinal cord injury. Notably, these in vivo effects of RO48 were seen in several independent experimental series performed in distinct laboratories at different times. Finally, in a cervical dorsal hemisection model, RO48 not only promoted growth of CST axons beyond the lesion, but also improved behavioral recovery in the rotarod, gridwalk, and pellet retrieval tasks. Our results provide strong evidence for RO48 as an effective compound to promote axon growth and regeneration. Further, they point to strategies for increasing robustness of interventions in pre-clinical models.
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DOI：
10.1038/nrd2999
发表时间：
2009-11
期刊：
Nature reviews. Drug discovery
影响因子：
--
作者：
通讯作者：
--
影响因子：
4.2
作者：
Forgione, Nicole;Chamankhah, Mahmood;Fehlings, Michael G.
通讯作者：
Fehlings, Michael G.
影响因子：
5.3
作者：
Fournier, AE;Takizawa, BT;Strittmatter, SM
通讯作者：
Strittmatter, SM
影响因子：
4
作者：
Al-Ali, Hassan;Schuerer, Stephan C.;Bixby, John L.
通讯作者：
Bixby, John L.
影响因子：
8.6
作者：
Gautam, Prson;Jaiswal, Alok;Wennerberg, Krister
通讯作者：
Wennerberg, Krister