The characterization of microtubule-stabilizing drugs as possible therapeutic agents for Alzheimer's disease and related tauopathies.
The characterization of microtubule-stabilizing drugs as possible therapeutic agents for Alzheimer's disease and related tauopathies.
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微管稳定药物的表征是阿尔茨海默氏病和相关tauopathies的治疗剂。
DOI：
10.1016/j.phrs.2010.12.002
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发表时间：
2011-04
影响因子：
9.3
通讯作者：
Lee, Virginia M. -Y.
中科院分区：
文献类型：
--
作者：
Brunden, Kurt R.;Yao, Yuemang;Potuzak, Justin S.;Ferrer, Nuria Ibarz;Ballatore, Carlo;James, Michael J.;Hogan, Anne-Marie L.;Trojanowski, John Q.;Smith, Amos B., III;Lee, Virginia M. -Y.
Tau是一种富含于中枢神经系统(CNS)1神经元中的蛋白质，被认为在微管(MTS)的稳定中发挥着关键作用。几种称为tau病的神经退行性疾病，包括阿尔茨海默病和某些类型的额颞叶变性，其特征是过度磷酸化的tau纤维在细胞内积累。Tau沉积到不可溶的聚集体中被认为会导致tau功能的丧失，从而导致MT的不稳定，这可能会导致神经变性，因为完整的MT是轴突运输和正常神经元功能所必需的。这种tau功能丧失假说已经在带有脊髓tau包涵体的tau转基因小鼠模型中得到验证，其中MT稳定剂紫杉醇增加了脊神经MT的密度，并改善了药物在神经肌肉接头吸收后的运动功能。遗憾的是，紫杉醇是一种P-糖蛋白底物，具有较差的血脑屏障通透性，不适合治疗人类肥胖症。因此，我们研究了几种来自紫杉烷和伊波硫酮天然产物家族的MT稳定化合物，以评估它们的膜通透性，并确定它们是作为P-糖蛋白的底物还是抑制剂。此外，我们还比较了给药后小鼠大脑和血浆中这些化合物的水平。最后，我们评估了脑渗透化合物是否具有稳定小鼠中枢神经系统MTS的作用。我们发现，几种埃博西酮的大脑渗透率明显高于紫杉烷。此外，某些埃博西酮类药物可提高中枢神经系统MT的稳定性，其中埃博西酮D表现出良好的药代动力学和药效学特征，提示该药作为一种潜在的相互作用药物候选药物值得进一步研究。
Tau, a protein that is enriched in neurons of the central nervous system (CNS)1, is thought to play a critical role in the stabilization of microtubules (MTs). Several neurodegenerative disorders referred to as tauopathies, including Alzheimer’s disease and certain types of frontotemporal lobar degeneration, are characterized by the intracellular accumulation of hyperphosphorylated tau fibrils. Tau deposition into insoluble aggregates is believed to result in a loss of tau function that leads to MT destabilization, and this could cause neurodegeneration as intact MTs are required for axonal transport and normal neuron function. This tau loss-of-function hypothesis has been validated in a tau transgenic mouse model with spinal cord tau inclusions, where the MT-stabilizing agent, paclitaxel, increased spinal nerve MT density and improved motor function after drug absorption at neuromuscular junctions. Unfortunately, paclitaxel is a P-glycoprotein substrate and has poor blood-brain barrier permeability, making it unsuitable for the treatment of human tauopathies. We therefore examined several MT-stabilizing compounds from the taxane and epothilone natural product families to assess their membrane permeability and to determine whether they act as substrates or inhibitors of P-glycoprotein. Moreover, we compared brain and plasma levels of the compounds after administration to mice. Finally, we assessed whether brain-penetrant compounds could stabilize mouse CNS MTs. We found that several epothilones have significantly greater brain penetration than the taxanes. Furthermore, certain epothilones cause an increase in CNS MT stabilization, with epothilone D demonstrating a favorable pharmacokinetic and pharmacodynamic profile which suggests this agent merits further study as a potential tauopathy drug candidate.
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