Reduced expression of brain-derived neurotrophic factor (BDNF) and impaired activation of the BDNF receptor, tropomyosin receptor kinase B (TrkB; also known as Ntrk2), are thought to contribute significantly to the pathophysiology of Rett syndrome (RTT), a severe neurodevelopmental disorder caused by loss-of-function mutations in the X-linked gene encoding methyl-CpG-binding protein 2 (MeCP2). Previous studies from this and other laboratories have shown that enhancing BDNF expression and/or TrkB activation in Mecp2-deficient mouse models of RTT can ameliorate or reverse abnormal neurological phenotypes that mimic human RTT symptoms. The present study reports on the preclinical efficacy of a novel, small-molecule, non-peptide TrkB partial agonist, PTX-BD4-3, in heterozygous female Mecp2 mutant mice, a well-established RTT model that recapitulates the genetic mosaicism of the human disease. PTX-BD4-3 exhibited specificity for TrkB in cell-based assays of neurotrophin receptor activation and neuronal cell survival and in in vitro receptor binding assays. PTX-BD4-3 also activated TrkB following systemic administration to wild-type and Mecp2 mutant mice and was rapidly cleared from the brain and plasma with a half-life of ∼2 h. Chronic intermittent treatment of Mecp2 mutants with a low dose of PTX-BD4-3 (5 mg/kg, intraperitoneally, once every 3 days for 8 weeks) reversed deficits in two core RTT symptom domains - respiration and motor control - and symptom rescue was maintained for at least 24 h after the last dose. Together, these data indicate that significant clinically relevant benefit can be achieved in a mouse model of RTT with a chronic intermittent, low-dose treatment paradigm targeting the neurotrophin receptor TrkB.

中文翻译：

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在用新型 TrkB 小分子激活剂长期治疗后，雷特综合征小鼠模型中运动学习的恢复。

脑源性神经营养因子 (BDNF) 的表达降低和 BDNF 受体原肌球蛋白受体激酶 B (TrkB；也称为 Ntrk2) 的激活受损，被认为对 Rett 综合征 (RTT) 的病理生理学有显着影响，这是一种严重的神经发育障碍由编码甲基 CpG 结合蛋白 2 (MeCP2) 的 X 连锁基因功能丧失突变引起的疾病。来自该实验室和其他实验室的先前研究表明，在Mecp2缺陷型 RTT 小鼠模型中增强 BDNF 表达和/或 TrkB 激活可以改善或逆转模拟人类 RTT 症状的异常神经表型。本研究报告了一种新型小分子非肽 TrkB 部分激动剂 PTX-BD4-3 在杂合雌性Mecp2 中的临床前疗效突变小鼠，这是一种完善的 RTT 模型，它概括了人类疾病的遗传嵌合现象。PTX-BD4-3 在神经营养因子受体激活和神经元细胞存活的基于细胞的测定以及体外受体结合测定中表现出对 TrkB 的特异性。在对野生型和Mecp2突变小鼠进行全身给药后，PTX-BD4-3 也激活了 TrkB ，并迅速从大脑和血浆中清除，半衰期约为 2 小时。Mecp2的慢性间歇治疗具有低剂量 PTX-BD4-3（5 毫克/公斤，腹膜内，每 3 天一次，持续 8 周）的突变体逆转了两个核心 RTT 症状域——呼吸和运动控制——的缺陷，并且症状挽救至少维持了 24最后一次给药后的小时。总之，这些数据表明，在 RTT 小鼠模型中，采用靶向神经营养因子受体 TrkB 的慢性间歇性低剂量治疗范式可以获得显着的临床相关益处。