MT-Stabilizer, Dictyostatin, Exhibits Prolonged Brain Retention and Activity: Potential Therapeutic Implications
MT-Stabilizer, Dictyostatin, Exhibits Prolonged Brain Retention and Activity: Potential Therapeutic Implications
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DOI：
10.1021/ml400233e
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发表时间：
2013-09-01
影响因子：
4.2
通讯作者：
Smith, Amos B., III
中科院分区：
文献类型：
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作者：
Brunden, Kurt R.;Gardner, Nicola M.;Smith, Amos B., III
在阿尔茨海默病和相关的神经退行性疾病患者的大脑神经元中发现了包含微管(MT)稳定蛋白tau的包涵体，这些疾病被广泛称为tauopathy。包裹体中的tau被认为是导致tau功能丧失的原因，导致MT的结构和功能受损，导致神经元损伤。最近的数据显示，脑穿透性MT稳定剂EpoD(EpoD)可以改善转基因小鼠的认知功能，减少神经元丢失和tau病理改变。因此，有必要确定其他具有血脑屏障(BBB)通透性和脑清除缓慢的MT稳定化合物，如EpoD所观察到的那样。我们在这里报道，MT稳定的天然产物Dtyostatin在小鼠中跨越血脑屏障，并延长了大脑保留时间。此外，给小鼠单次给药可以延长MTS在大脑中的稳定时间。相比之下，结构上相关的MT稳定剂，盘状避孕药，显示出明显较少的脑暴露。因此，Dityostatin作为一种潜在的肌病治疗方法值得进一步研究。
Inclusions comprising the microtubule (MT)stabilizing protein, tau, are found within neurons in the brains of patients with Alzheimer's disease and related neuro-degenerative disorders that are broadly referred to as tauopathies. The sequestration of tau into inclusions is believed to cause a loss of tau function, such that MT structure and function are compromised, leading to neuronal damage. Recent data reveal that the brain-penetrant MT-stabilizing agent, epothilone D (EpoD), improves cognitive function and decreases both neuron loss and tau pathology in transgenic mouse models of tauopathy. There is thus a need to identify additional MT-stabilizing compounds with blood brain barrier (BBB) permeability and slow brain clearance, as observed with EpoD. We report here that the MT-stabilizing natural product, dictyostatin, crosses the BBB in mice and has extended brain retention. Moreover, a single administration of dictyostatin to mice causes prolonged stabilization of MTs in the brain. In contrast, the structurally related MT-stabilizer, discodermolide, shows significantly less brain exposure. Thus, dictyostatin merits further investigation as a potential tauopathy therapeutic.