Menzies Institute for Medical Research, University of Tasmania 17 Liverpool Street Hobart, Tasmania, 7000, Australia.
Sci Rep. 2020 Jan 22;10(1):918. doi: 10.1038/s41598-020-57718-z.
Brain penetrant microtubule stabilising agents (MSAs) are being increasingly validated as potential therapeutic strategies for neurodegenerative diseases and traumatic injuries of the nervous system. MSAs are historically used to treat malignancies to great effect. However, this treatment strategy can also cause adverse off-target impacts, such as the generation of debilitating neuropathy and axonal loss. Understanding of the effects that individual MSAs have on neurons of the central nervous system is still incomplete. Previous research has revealed that aberrant microtubule stabilisation can perturb many neuronal functions, such as neuronal polarity, neurite outgrowth, microtubule dependant transport and overall neuronal viability. In the current study, we evaluate the dose dependant impact of epothilone D, a brain penetrant MSA, on both immature and relatively mature mouse cortical neurons in vitro. We show that epothilone D reduces the viability, growth and complexity of immature cortical neurons in a dose dependant manner. Furthermore, in relatively mature cortical neurons, we demonstrate that while cellularly lethal doses of epothilone D cause cellular demise, low sub lethal doses can also affect mitochondrial transport over time. Our results reveal an underappreciated mitochondrial disruption over a wide range of epothilone D doses and reiterate the importance of understanding the dosage, timing and intended outcome of MSAs, with particular emphasis on brain penetrant MSAs being considered to target neurons in disease and trauma.
脑穿透微管稳定剂 (MSAs) 作为神经退行性疾病和神经系统创伤的潜在治疗策略，其有效性正得到越来越多的验证。MSAs 历史上被用于治疗恶性肿瘤，效果显著。然而，这种治疗策略也可能产生不良的脱靶影响，例如产生使人衰弱的神经病变和轴突丧失。人们对个体 MSA 对中枢神经系统神经元的影响的了解仍然不完整。先前的研究表明，异常的微管稳定会扰乱许多神经元功能，如神经元极性、突起生长、微管依赖的运输和整体神经元活力。在本研究中，我们评估了脑穿透 MSA 埃坡霉素 D 对体外未成熟和相对成熟的小鼠皮质神经元的剂量依赖性影响。我们表明，埃坡霉素 D 以剂量依赖性方式降低未成熟皮质神经元的活力、生长和复杂性。此外，在相对成熟的皮质神经元中，我们证明虽然细胞致死剂量的埃坡霉素 D 会导致细胞死亡，但低亚致死剂量也会随时间影响线粒体运输。我们的结果揭示了埃坡霉素 D 广泛剂量范围内未被充分认识的线粒体破坏，并再次强调了理解 MSA 的剂量、时间和预期结果的重要性，特别是对于被认为可以靶向疾病和创伤中神经元的脑穿透 MSA 更是如此。
