Brain-penetrant microtubule-stabilizing compounds as potential therapeutic agents for tauopathies.
Brain-penetrant microtubule-stabilizing compounds as potential therapeutic agents for tauopathies.
复制标题
脑培训微管稳定化合物作为对呼吸病的潜在治疗剂。
DOI：
10.1042/bst20120010
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发表时间：
2012-08
影响因子：
3.9
通讯作者：
Trojanowski JQ
中科院分区：
文献类型：
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作者：
Brunden KR;Ballatore C;Lee VM;Smith AB 3rd;Trojanowski JQ
阿尔茨海默病(AD)和相关神经退行性疾病患者大脑中的神经元，统称为tauopathies，含有由过度磷酸化的tau蛋白组成的纤维状包涵体。Tau通常富含轴突，在那里它结合并稳定MTS(微管)。Tau蛋白过度磷酸化和聚集可能导致MT结合减少，从而影响轴突运输和神经元功能。克服tau功能丧失的一种可能的治疗策略是给予MT稳定剂，如用于癌症治疗的那些。然而，这些药物都会产生严重的副作用，而且现有的大多数MT稳定化合物的血脑屏障(BBB)通透性都很差，这使得它们不适合于推拿疗法。我们确定EpoD(Epothilone D)是一种脑穿透性MT稳定剂，具有良好的药代动力学和药效学特性。在已建立的转基因小鼠模型中，使用预防性和干预性给药范例，评估了EpoD对tau功能丧失的补偿能力。EpoD的剂量比以前在人类癌症患者中使用的剂量低得多，可以改善tau TG小鼠的轴突MT密度，减少轴突营养不良，从而缓解认知缺陷。此外，EpoD还减轻了老年tau-TG小鼠tau的病理程度。重要的是，在EpoD处理的小鼠中没有观察到不良副作用。这些结果表明EpoD可能是治疗AD和相关疾病的一种可行的候选药物。
Neurons within the brains of those with AD (Alzheimer’s disease) and related neurodegenerative disorders, collectively termed ‘tauopathies’, contain fibrillar inclusions composed of hyperphosphorylated tau protein. Tau is normally enriched in axons, where it binds and stabilizes MTs (microtubules). Tau hyperphosphorylation and aggregation probably result in reduced MT binding that could affect axonal transport and neuronal function. A possible therapeutic strategy to overcome a loss of tau function in tauopathies is administration of MT-stabilizing agents, such as those used in the treatment of cancer. However, these drugs elicit severe side effects, and most existing MT-stabilizing compounds have poor BBB (blood–brain barrier) permeability, which renders them unsuitable for tauopathy treatment. We identified EpoD (epothilone D) as a brain-penetrant MT-stabilizing agent with preferred pharmacokinetic and pharmacodynamic properties. EpoD was evaluated for its ability to compensate for tau loss-of-function in an established Tg (transgenic) mouse model, using both preventative and interventional dosing paradigms. EpoD at doses much lower than previously used in human cancer patients caused improved axonal MT density and decreased axonal dystrophy in the tau Tg mice, leading to an alleviation of cognitive deficits. Moreover, EpoD reduced the extent of tau pathology in aged tau Tg mice. Importantly, no adverse side effects were observed in the EpoD-treated mice. These results suggest that EpoD might be a viable drug candidate for the treatment of AD and related tauopathies.