Dichloroacetate causes reversible demyelination in vitro:: potential mechanism for its neuropathic effect
Dichloroacetate causes reversible demyelination in vitro:: potential mechanism for its neuropathic effect
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DOI：
10.1111/j.1471-4159.2006.04248.x
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发表时间：
2007-01-01
影响因子：
4.7
通讯作者：
Notterpek, Lucia
中科院分区：
文献类型：
--
作者：
Felitsyn, Natalia;Stacpoole, Peter W.;Notterpek, Lucia
二氯乙酸酯(DCA)是一种治疗遗传性线粒体疾病的研究药物，其使用已被可逆性周围神经病变缓解。我们利用培养的大鼠雪旺细胞(SCs)和背根神经节(DRG)神经元，研究了DCA的神经毒性机制。髓鞘SC-DRG神经元共培养，分离的SCs和DRG神经元暴露于1~20 mMDCA中，最长12天。髓鞘碱性蛋白(MBP)、蛋白零(P0)、髓鞘相关糖蛋白(MAG)和外周髓鞘蛋白22(PMP22)的免疫标记和免疫印迹显示，在髓鞘共培养中，DCA引起髓鞘形成的减少，呈剂量和暴露依赖性。经过10天的DCA洗涤后，髓鞘部分恢复。DCA不影响中间丝蛋白的稳态水平，但促进了抗神经丝抗体反应性旋涡的形成。在分离的SC培养中，与未经DCA处理的样品相比，DCA降低了P0和PMP22的表达，而增加了神经营养素受体p75(NTR)的水平。根据乳酸脱氢酶的释放，DCA对神经细胞和神经胶质细胞的活力有轻微的不良影响。这些结果表明，DCA诱导了髓鞘相关蛋白的可逆性抑制，这可能至少部分解释了其临床周围神经病变效应。
Dichloroacetate (DCA) is an investigational drug for genetic mitochondrial diseases whose use has been mitigated by reversible peripheral neuropathy. We investigated the mechanism of DCA neurotoxicity using cultured rat Schwann cells (SCs) and dorsal root ganglia (DRG) neurons. Myelinating SC-DRG neuron co-cultures, isolated SCs and DRG neurons were exposed to 1-20 mM DCA for up to 12 days. In myelinating co-cultures, DCA caused a dose- and exposure-dependent decrease of myelination, as determined by immunolabeling and immunoblotting for myelin basic protein (MBP), protein zero (P0), myelin-associated glycoprotein (MAG) and peripheral myelin protein 22 (PMP22). Partial recovery of myelination occurred following a 10-day washout of DCA. DCA did not affect the steady-state levels of intermediate filament proteins, but promoted the formation of anti-neurofilament antibody reactive whirls. In isolated SC cultures, DCA decreased the expression of P0 and PMP22, while it increased the levels of p75(NTR) (neurotrophin receptor), as compared with non-DCA-treated samples. DCA had modest adverse effects on neuronal and glial cell vitality, as determined by the release of lactate dehydrogenase. These results demonstrate that DCA induces a reversible inhibition of myelin-related proteins that may account, at least in part, for its clinical peripheral neuropathic effects.