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首页> 外文期刊>Neuron >A Peptide Uncoupling BDNF Receptor TrkB from Phospholipase C gamma 1 Prevents Epilepsy Induced by Status Epilepticus
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A Peptide Uncoupling BDNF Receptor TrkB from Phospholipase C gamma 1 Prevents Epilepsy Induced by Status Epilepticus

机译：从磷脂酶Cγ1的肽解耦BDNF受体TrkB预防癫痫持续状态引起的癫痫病。

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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 C gamma 1 (PLC gamma 1) is the dominant signaling effector by which excessive activation of TrkB promotes epilepsy. We designed a novel peptide (pY816) that uncouples TrkB from PLCg1. 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.
机译：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。癫痫持续状态引起的TrkB过度激活促进颞叶癫痫（TLE）的发展，揭示TrkB作为预防TLE的治疗靶点。为了避免总体抑制TrkB信号传导的不良后果，我们实施了一种旨在选择性抑制负责TLE的TrkB激活信号通路的新策略。我们对小鼠模型的研究表明，磷脂酶Cγ1（PLCγ1）是主要的信号转导因子，通过该因子过度激活TrkB可以促进癫痫发作。我们设计了一种新型肽（pY816），可将TrkB与PLCg1解偶联。癫痫持续状态后用pY816进行治疗可抑制TLE，并预防焦虑样疾病，但仍保留内源性TrkB信号传导的神经保护作用。我们提供了针对受体酪氨酸信号转导的新策略的概念验证证据，并确定了有望预防人类癫痫持续状态引起的TLE的疗法。

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