The Microtubule-Modulating Drug Epothilone D Alters Dendritic Spine Morphology in a Mouse Model of Mild Traumatic Brain Injury.
The Microtubule-Modulating Drug Epothilone D Alters Dendritic Spine Morphology in a Mouse Model of Mild Traumatic Brain Injury.
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DOI：
10.3389/fncel.2018.00223
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发表时间：
2018
影响因子：
5.3
通讯作者：
Dickson TC
中科院分区：
文献类型：
--
作者：
Chuckowree JA;Zhu Z;Brizuela M;Lee KM;Blizzard CA;Dickson TC
微管动力学在中枢神经系统复杂的发育、结构、功能和维持过程中起着重要的作用。在损伤的脑内，微管容易在神经元中错位和溶解，并参与损伤诱导的神经胶质反应和损伤后的适应性神经可塑性。不幸的是，目前缺乏治疗创伤性脑损伤(TBI)的治疗选择。因此，利用临床相关的Thy1-YFPH雄性小鼠轻度脑外伤模型，我们研究了脑穿透性微管稳定剂Epothilone D的潜在治疗效果。在单次轻度外侧脑损伤后7天，同侧大脑半球以轻度星形胶质细胞激活和内囊和外囊白质束轴突损伤为典型且广泛的模式为特征。这些改变发生在没有其他明显创伤迹象的情况下：皮质厚度或表达YFP的皮质投射神经元、轴突或树突的数量没有改变。有趣的是，在FPI(和假手术)后立即给予单次小剂量的Epothilone D可引起第5层皮质投射神经元树突棘的显著改变，而星形胶质细胞的反应和轴突的病理变化不受影响。具体地说，经Epothilone D处理后，刺长度显著缩短，而蘑菇刺密度显著增加。综上所述，这些发现对微管稳定剂在操纵损伤诱导的突触可塑性中的使用具有重要意义，并表明进一步研究微管稳定剂作为抗脑损伤治疗策略的可行性是必要的。
Microtubule dynamics underpin a plethora of roles involved in the intricate development, structure, function, and maintenance of the central nervous system. Within the injured brain, microtubules are vulnerable to misalignment and dissolution in neurons and have been implicated in injury-induced glial responses and adaptive neuroplasticity in the aftermath of injury. Unfortunately, there is a current lack of therapeutic options for treating traumatic brain injury (TBI). Thus, using a clinically relevant model of mild TBI, lateral fluid percussion injury (FPI) in adult male Thy1-YFPH mice, we investigated the potential therapeutic effects of the brain-penetrant microtubule-stabilizing agent, epothilone D. At 7 days following a single mild lateral FPI the ipsilateral hemisphere was characterized by mild astroglial activation and a stereotypical and widespread pattern of axonal damage in the internal and external capsule white matter tracts. These alterations occurred in the absence of other overt signs of trauma: there were no alterations in cortical thickness or in the number of cortical projection neurons, axons or dendrites expressing YFP. Interestingly, a single low dose of epothilone D administered immediately following FPI (and sham-operation) caused significant alterations in the dendritic spines of layer 5 cortical projection neurons, while the astroglial response and axonal pathology were unaffected. Specifically, spine length was significantly decreased, whereas the density of mushroom spines was significantly increased following epothilone D treatment. Together, these findings have implications for the use of microtubule stabilizing agents in manipulating injury-induced synaptic plasticity and indicate that further study into the viability of microtubule stabilization as a therapeutic strategy in combating TBI is warranted.
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