Delayed administration of a small molecule tropomyosin-related kinase B ligand promotes recovery after hypoxic-ischemic stroke.
Delayed administration of a small molecule tropomyosin-related kinase B ligand promotes recovery after hypoxic-ischemic stroke.
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DOI：
10.1161/strokeaha.111.641878
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发表时间：
2012-07
期刊：
影响因子：
8.3
通讯作者：
Buckwalter MS
中科院分区：
文献类型：
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作者：
Han J;Pollak J;Yang T;Siddiqui MR;Doyle KP;Taravosh-Lahn K;Cekanaviciute E;Han A;Goodman JZ;Jones B;Jing D;Massa SM;Longo FM;Buckwalter MS
在美国，中风是导致长期残疾的主要原因，但没有药物被证明可以改善恢复。脑源性神经营养因子（BDNF）刺激神经发生和可塑性，这些过程与中风恢复有关。与原肌球蛋白相关激酶B（Trk B）和p75神经营养因子（p75 NTR）受体结合。然而，BDNF不是一种可行的治疗剂，并且不存在可以复制其与两种受体结合的小分子。我们测试了选择性靶向TrkB的小分子（LM 22 A-4）将促进中风后神经发生和功能恢复的假设。四个月大的小鼠在中风前接受运动任务训练。中风后，功能测试结果被用于将小鼠随机分为两个同等严重受损的组。在中风后3天开始，小鼠每天接受LM 22 A-4或盐水媒介物，持续10周。LM 22 A-4治疗显著改善了肢体摆动速度，并加速了中风后恢复正常步态准确性。LM 22 A-4治疗还使中风附近的新的成熟神经元和未成熟神经元的数量加倍。在血管生成、树突状分支、轴突发芽、胶质瘢痕形成或神经炎症方面未观察到药物诱导的差异。TrkB的小分子激动剂在中风后三天开始施用时改善中风的功能恢复并增加神经发生。这些发现提供了概念验证，即单独靶向TrkB能够促进与中风恢复相关的一种或多种机制。因此，LM 22 A-4或其衍生物可用作中风的“促恢复”治疗剂。
Stroke is the leading cause of long-term disability in the United States, yet no drugs are available that are proven to improve recovery. Brain-derived neurotrophic factor (BDNF) stimulates neurogenesis and plasticity, processes that are implicated in stroke recovery. It binds to both the tropomyosin-related kinase B (TrkB) and p75 neurotrophin (p75NTR) receptors. However, BDNF is not a feasible therapeutic agent, and no small molecule exists that can reproduce its binding to both receptors. We tested the hypothesis that a small molecule (LM22A-4) that selectively targets TrkB would promote neurogenesis and functional recovery after stroke. Four-month-old mice were trained on motor tasks prior to stroke. After stroke, functional test results were used to randomize mice into two equally, and severely, impaired groups. Beginning 3 days after stroke, mice received LM22A-4 or saline vehicle daily for ten weeks. LM22A-4 treatment significantly improved limb swing speed and accelerated the return to normal gait accuracy after stroke. LM22A-4 treatment also doubled both the number of new mature neurons and immature neurons adjacent to the stroke. Drug-induced differences were not observed in angiogenesis, dendritic arborization, axonal sprouting, glial scar formation, or neuroinflammation. A small molecule agonist of TrkB improves functional recovery from stroke and increases neurogenesis when administered beginning three days after stroke. These findings provide proof-of-concept that targeting of TrkB alone is capable of promoting one or more mechanisms relevant to stroke recovery. LM22A-4 or its derivatives might therefore serve as “pro-recovery” therapeutic agents for stroke.