Autotaxin and lysophosphatidic acid1 receptor-mediated demyelination of dorsal root fibers by sciatic nerve injury and intrathecal lysophosphatidylcholine.
Autotaxin and lysophosphatidic acid1 receptor-mediated demyelination of dorsal root fibers by sciatic nerve injury and intrathecal lysophosphatidylcholine.
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DOI：
10.1186/1744-8069-6-78
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发表时间：
2010-11-09
期刊：
影响因子：
3.3
通讯作者：
Ueda H
中科院分区：
文献类型：
--
作者：
Nagai J;Uchida H;Matsushita Y;Yano R;Ueda M;Niwa M;Aoki J;Chun J;Ueda H
虽然神经性疼痛经常在脱髓鞘疾病如格林-巴利综合征和多发性硬化症中观察到，但脱髓鞘和神经性疼痛行为之间关系的分子基础知之甚少。以前，我们发现溶血磷脂酸受体（LPA 1）信号启动坐骨神经损伤诱导的神经病理性疼痛和脱髓鞘。在本研究中，我们已经证明，坐骨神经损伤诱导明显的脱髓鞘伴随着髓鞘相关糖蛋白（MAG）下调和损伤的雪旺细胞分区的C-纤维包含Remak束在坐骨神经和背根，但不是在脊神经。在LPA 1受体缺陷（Lpar 1-/-）小鼠中，背根中的脱髓鞘、MAG下调和Remak束损伤被消除，但在坐骨神经中未观察到这些改变。然而，在离体实验中，在坐骨神经、脊神经和背根中观察到LPA诱导的脱髓鞘，所有这些都表达LPA 1转录物和蛋白。神经损伤诱导的背根脱髓鞘在自分泌运动因子（atx+/-）杂合子小鼠中显著减弱，自分泌运动因子将溶血磷脂酰胆碱（LPC）转化为LPA。尽管在存在重组ATX的情况下将LPC添加到背根纤维的离体培养物中引起有效的脱髓鞘，但在不存在ATX的情况下其没有显著作用。另一方面，鞘内注射LPC引起有效的背根脱髓鞘，这在atx+/-或Lpar 1-/-小鼠中显著减弱或消除。这些结果表明，由ATX从LPC转化的LPA激活LPA 1受体并诱导神经损伤后的背根脱髓鞘，这导致神经病理性疼痛。
Although neuropathic pain is frequently observed in demyelinating diseases such as Guillain-Barré syndrome and multiple sclerosis, the molecular basis for the relationship between demyelination and neuropathic pain behaviors is poorly understood. Previously, we found that lysophosphatidic acid receptor (LPA1) signaling initiates sciatic nerve injury-induced neuropathic pain and demyelination. In the present study, we have demonstrated that sciatic nerve injury induces marked demyelination accompanied by myelin-associated glycoprotein (MAG) down-regulation and damage of Schwann cell partitioning of C-fiber-containing Remak bundles in the sciatic nerve and dorsal root, but not in the spinal nerve. Demyelination, MAG down-regulation and Remak bundle damage in the dorsal root were abolished in LPA1 receptor-deficient (Lpar1-/-) mice, but these alterations were not observed in sciatic nerve. However, LPA-induced demyelination in ex vivo experiments was observed in the sciatic nerve, spinal nerve and dorsal root, all which express LPA1 transcript and protein. Nerve injury-induced dorsal root demyelination was markedly attenuated in mice heterozygous for autotaxin (atx+/-), which converts lysophosphatidylcholine (LPC) to LPA. Although the addition of LPC to ex vivo cultures of dorsal root fibers in the presence of recombinant ATX caused potent demyelination, it had no significant effect in the absence of ATX. On the other hand, intrathecal injection of LPC caused potent dorsal root demyelination, which was markedly attenuated or abolished in atx+/- or Lpar1-/- mice. These results suggest that LPA, which is converted from LPC by ATX, activates LPA1 receptors and induces dorsal root demyelination following nerve injury, which causes neuropathic pain.
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DOI：
10.1083/jcb.135.4.1071
发表时间：
1996-11
期刊：
The Journal of cell biology
影响因子：
--
作者：
Hecht JH;Weiner JA;Post SR;Chun J
通讯作者：
Chun J
影响因子：
7.4
作者：
Ahn, Dong K.;Lee, Sang Y.;Bae, Yong C.
通讯作者：
Bae, Yong C.
DOI：
10.1073/pnas.97.24.13384
发表时间：
2000-11-21
影响因子：
11.1
作者：
Contos, JJA;Fukushima, N;Chun, J
通讯作者：
Chun, J
影响因子：
5.3
作者：
Gupta, Ranjan;Rummler, Laura S.;Steward, Oswald
通讯作者：
Steward, Oswald
影响因子：
4.2
作者：
Fujita, Ryousuke;Kiguchi, Norikazu;Ueda, Hiroshi
通讯作者：
Ueda, Hiroshi