Epothilone D prevents binge methamphetamine-mediated loss of striatal dopaminergic markers.
Epothilone D prevents binge methamphetamine-mediated loss of striatal dopaminergic markers.
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DOI：
10.1111/jnc.13391
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发表时间：
2016-02
影响因子：
4.7
通讯作者：
Moszczynska A
中科院分区：
文献类型：
--
作者：
Killinger BA;Moszczynska A
暴露于过量甲基苯丙胺（METH）可导致纹状体中多巴胺（DA）、多巴胺转运蛋白（DAT）和酪氨酸羟化酶（TH）等多巴胺能（DA能）标记物的永久或短暂丧失。我们假设，甲硫氨酸诱导的纹状体DA能标记物的损失，部分是由于在黑质纹状体DA通路中的微管（MT）的不稳定，最终阻碍这些标记物的顺行轴突运输。为了验证这一假设，在存在或不存在埃博霉素D（EpoD）（一种MT稳定化合物）的情况下，用METH或盐水对成年雄性Sprague道利大鼠进行了治疗，并在治疗后3天评估了几种DA能标记物的水平以及微管蛋白及其翻译后修饰（PMT）的水平。过量的甲基苯丙胺导致纹状体内稳定的长寿命MT的丢失，但不在SNPC内。用低剂量的EpoD治疗增加了稳定MT的标记物的水平，并防止了纹状体中几种DA能标记物的MET介导的缺陷。相比之下，给予高剂量的EpoD似乎使MT不稳定，并增强了几种DA能标记物中的MET诱导的缺陷。低剂量的EpoD也防止了METH治疗期间METH诱导的纹状体DA周转增加和行为刻板性增加。总之，这些结果表明，MT动力学发挥了作用，在纹状体中的几个DA能标记物的METH诱导的损失的发展，并可能介导METH诱导的黑质纹状体DA通路的终端退化。我们的研究还表明，MT稳定药物，如EpoD有潜力作为有用的治疗剂，以恢复功能的DA能神经末梢后，METH暴露时，以低剂量给药。大量使用甲基苯丙胺（METH）会对黑质纹状体多巴胺（DA）系统的神经传递产生负面影响。METH的作用包括降低纹状体中DA能标记物的水平。我们已经确定，高剂量METH使该途径中的微管不稳定，表现为乙酰化（Acetyl）和脱酪氨酸（Detyr）α-微管蛋白水平降低。微管稳定剂埃坡霉素D保护纹状体微管免受METH的侵害。这些发现提供了一个新的策略，保护免受甲基-恢复适当的轴突运输。
Exposure to binge methamphetamine (METH) can result in a permanent or transient loss of dopaminergic (DAergic) markers such as dopamine (DA), dopamine transporter (DAT), and tyrosine hydroxylase (TH) in the striatum. We hypothesized that the METH-induced loss of striatal DAergic markers was, in part, due to destabilization of microtubules (MTs) in the nigrostriatal DA pathway that ultimately impedes anterograde axonal transport of these markers. To test this hypothesis, adult male Sprague Dawley rats were treated with binge METH or saline in the presence or absence of epothilone D (EpoD), a MT-stabilizing compound, and assessed for the levels of several DAergic markers as well as for the levels of tubulins and their posttranslational modifications (PMTs) at 3 days after the treatments. Binge METH induced a loss of stable long-lived MTs within the striatum but not within the SNpc. Treatment with a low dose of EpoD increased the levels of markers of stable MTs and prevented METH-mediated deficits in several DAergic markers in the striatum. By contrast, administration of a high dose of EpoD appeared to destabilize MTs and potentiated the METH-induced deficits in several DAergic markers. The low-dose EpoD also prevented the METH-induced increase in striatal DA turnover and increased behavioral stereotypy during METH treatment. Together, these results demonstrate that MT dynamics plays a role in the development of METH-induced losses of several DAergic markers in the striatum and may mediate METH-induced degeneration of terminals in the nigrostriatal DA pathway. Our study also demonstrates that MT-stabilizing drugs, such as EpoD have a potential to serve as useful therapeutic agents to restore function of DAergic nerve terminals following METH exposure when administered at low doses. Administration of binge methamphetamine (METH) negatively impacts neurotransmission in the nigrostriatal dopamine (DA) system. The effects of METH include decreasing the levels of DAergic markers in the striatum. We have determined that high-dose METH destabilizes microtubules in this pathway, which is manifested by decreased levels of acetylated (Acetyl) and detyrosinated (Detyr) α-tubulin. A microtubule stabilizing agent epothilone D protects striatal microtubules form METH. These findings provide a new strategy for protection form METH - restoration of proper axonal transport.