A Peptide Uncoupling BDNF Receptor TrkB from Phospholipase Cγ1 Prevents Epilepsy Induced by Status Epilepticus.
A Peptide Uncoupling BDNF Receptor TrkB from Phospholipase Cγ1 Prevents Epilepsy Induced by Status Epilepticus.
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DOI：
10.1016/j.neuron.2015.09.032
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发表时间：
2015-11-04
期刊：
影响因子：
16.2
通讯作者：
McNamara JO
中科院分区：
文献类型：
--
作者：
Gu B;Huang YZ;He XP;Joshi RB;Jang W;McNamara JO
BDNF受体酪氨酸激酶TrkB是健康和疾病中神经系统功能的基础。由癫痫持续状态引起的TrkB的过度激活促进了颞叶癫痫（TLE）的发展，揭示了TrkB作为预防TLE的治疗靶点。为了避免TrkB信号传导的全局抑制的不良后果，我们实施了一种新的策略，旨在选择性抑制负责TLE的TrkB激活的信号传导途径。我们对小鼠模型的研究表明，磷脂酶Cγ1（PLCγ1）是TrkB过度激活促进癫痫的主要信号效应子。我们设计了一种新的肽（pY816），其将TrkB与PLCγ1解偶联。在癫痫持续状态后用pY816治疗抑制TLE并预防焦虑样障碍，但保留内源性TrkB信号传导的神经保护作用。我们为靶向受体酪氨酸信号传导的新策略提供了概念验证证据，并确定了一种有望预防人类癫痫持续状态引起的TLE的治疗方法。
The BDNF receptor tyrosine kinase, TrkB, underlies nervous system function in both health and disease. Excessive activation of TrkB caused by status epilepticus promotes development of temporal lobe epilepsy (TLE), revealing TrkB as a therapeutic target for prevention of TLE. To circumvent undesirable consequences of global inhibition of TrkB signaling, we implemented a novel strategy aimed at selective inhibition of the TrkB-activated signaling pathway responsible for TLE. Our studies of a mouse model reveal that phospholipase Cγ1 (PLCγ1) is the dominant signaling effector by which excessive activation of TrkB promotes epilepsy. We designed a novel peptide (pY816) that uncouples TrkB from PLCγ1. Treatment with pY816 following status epilepticus inhibited TLE and prevented anxiety-like disorder yet preserved neuroprotective effects of endogenous TrkB signaling. We provide proof-of-concept evidence for a novel strategy targeting receptor tyrosine signaling and identify a therapeutic with promise for prevention of TLE caused by status epilepticus in humans.