Peripheral neuropathy in rats exposed to dichloroacetate.
Peripheral neuropathy in rats exposed to dichloroacetate.
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DOI：
10.1097/nen.0b013e3181b40217
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发表时间：
2009-09
影响因子：
3.2
通讯作者：
Stacpoole PW
中科院分区：
文献类型：
--
作者：
Calcutt NA;Lopez VL;Bautista AD;Mizisin LM;Torres BR;Shroads AL;Mizisin AP;Stacpoole PW
二氯乙酸酯(DCA)用于治疗线粒体疾病的患者受到诱导周围神经病变的限制。DCA所致神经病变的机制尚不清楚。口服DCA(50-500 mg/kg/天，长达16周)可诱发幼年和成年大鼠的触觉异常痛觉；高剂量时可同时出现热痛觉减退。用DCA治疗的幼年和成年大鼠都出现了神经传导减慢，成年大鼠的神经传导减慢更为明显。DCA处理的大鼠周围神经或脊髓内未发现明显的轴突或神经胶质细胞异常，但形态计量学分析显示周围神经有髓纤维的平均轴突直径减少。DCA治疗还导致氧化应激标志物在神经中积累。这些数据表明，无论是幼年大鼠还是成年大鼠，在与临床使用剂量相似的剂量下，都可以诱导出周围神经病变的行为、功能和结构指标。DCA诱导的周围神经病变主要累及轴突，涉及代谢和结构障碍。DCA治疗的大鼠可以深入了解周围神经病变的发病机制，并促进辅助治疗的发展，以预防目前限制DCA临床使用的这种疾病。
The use of dichloroacetate (DCA) for treating patients with mitochondrial diseases is limited by the induction of peripheral neuropathy. The mechanisms of DCA-induced neuropathy are not known. Oral DCA treatment (50–500 mg/kg/day for up to 16 weeks) induced tactile allodynia in both juvenile and adult rats; concurrent thermal hypoalgesia developed at higher doses. Both juvenile and adult rats treated with DCA developed nerve conduction slowing that was more pronounced in adult rats. No overt axonal or glial cell abnormalities were identified in peripheral nerves or spinal cord of any DCA-treated rats but morphometric analysis identified a reduction of mean axonal caliber of peripheral nerve myelinated fibers. DCA treatment also caused accumulation of oxidative stress markers in the nerves. These data indicate that behavioral, functional and structural indices of peripheral neuropathy may be induced in both juvenile and adult rats treated with DCA at doses similar to those in clinical use. DCA-induced peripheral neuropathy primarily afflicts axons and involves both metabolic and structural disorders. The DCA-treated rat may provide insight into the pathogenesis of peripheral neuropathy and facilitate development of adjuvant therapeutics to prevent this disorder that currently restricts the clinical use of DCA.