<br>预防 BDNF 受体 TrkB-FL 的兴奋性毒性诱导的加工可导致中风神经保护。,EMBO Molecular Medicine

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预防 BDNF 受体 TrkB-FL 的兴奋性毒性诱导的加工可导致中风神经保护。
EMBO Molecular Medicine ( IF 9.0 ) Pub Date : 2019-06-03 , DOI: 10.15252/emmm.201809950
Gonzalo S Tejeda ₁ , Gema M Esteban-Ortega ₁ , Esther San Antonio ₁ , Óscar G Vidaurre ₁ , Margarita Díaz-Guerra ₁

Affiliation

旨在通过药物治疗中风（死亡、残疾和痴呆的主要原因）的神经保护策略仍然难以捉摸。一种有前途的方法是通过增强脑源性神经营养因子（BDNF）启动的生存途径来限制梗塞半暗带中的兴奋性毒性神经元死亡。然而，缺血后神经营养信号传导的增强受到 BDNF 高亲和力受体、全长原肌球蛋白相关激酶 B (TrkB-FL) 下调的挑战，原因是钙蛋白酶降解，以及其次是调节的膜内蛋白水解。在这里，我们设计了一种含有 TrkB-FL 序列 (TFL457) 的血脑屏障 (BBB) 渗透性肽，可防止兴奋性毒性后早期诱导的受体从神经元表面消失。通过这种方式，TFL457 干扰两个蛋白水解系统对 TrkB-FL 的裂解，并通过 PLCγ 依赖性机制增加神经元活力。通过保留下游 CREB 和 MEF2 启动子活性，TFL457 启动反馈机制，有利于提高兴奋毒性神经元中关键的促存活 mRNA 和蛋白质的水平。这种神经保护肽可能与中风治疗高度相关，因为在小鼠缺血模型中，它可以抵消梗塞大脑中 TrkB-FL 的下调，有效减少梗塞面积并改善神经系统结果。

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Prevention of excitotoxicity-induced processing of BDNF receptor TrkB-FL leads to stroke neuroprotection.

Neuroprotective strategies aimed to pharmacologically treat stroke, a prominent cause of death, disability, and dementia, have remained elusive. A promising approach is restriction of excitotoxic neuronal death in the infarct penumbra through enhancement of survival pathways initiated by brain-derived neurotrophic factor (BDNF). However, boosting of neurotrophic signaling after ischemia is challenged by downregulation of BDNF high-affinity receptor, full-length tropomyosin-related kinase B (TrkB-FL), due to calpain-degradation, and, secondarily, regulated intramembrane proteolysis. Here, we have designed a blood-brain barrier (BBB) permeable peptide containing TrkB-FL sequences (TFL457 ) which prevents receptor disappearance from the neuronal surface, early induced after excitotoxicity. In this way, TFL457 interferes TrkB-FL cleavage by both proteolytic systems and increases neuronal viability via a PLCγ-dependent mechanism. By preserving downstream CREB and MEF2 promoter activities, TFL457 initiates a feedback mechanism favoring increased levels in excitotoxic neurons of critical prosurvival mRNAs and proteins. This neuroprotective peptide could be highly relevant for stroke therapy since, in a mouse ischemia model, it counteracts TrkB-FL downregulation in the infarcted brain, efficiently decreases infarct size, and improves neurological outcome.

更新日期：2019-07-05

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