Calpain-mediated down-regulation of myelin-associated glycoprotein in lysophosphatidic acid-induced neuropathic pain.
Calpain-mediated down-regulation of myelin-associated glycoprotein in lysophosphatidic acid-induced neuropathic pain.
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DOI：
10.1111/j.1471-4159.2010.06664.x
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发表时间：
2010-05
影响因子：
4.7
通讯作者：
Ueda H
中科院分区：
文献类型：
--
作者：
Xie W;Uchida H;Nagai J;Ueda M;Chun J;Ueda H
溶血磷脂酸受体（LPA 1）信号传导通过背根（DR）的脱髓鞘引发神经性疼痛。虽然发现LPA引起脱髓鞘的髓鞘蛋白的下调，但详细的机制仍有待确定。在目前的研究中，我们发现，一个单一的鞘内（i.t.）注射LPA通过LPA 1受体引起DR中髓鞘相关糖蛋白（MAG）的剂量和时间依赖性下调。在离体DR培养物中也观察到类似的事件。钙蛋白酶抑制剂X、E-64和E-64 d可显著抑制LPA诱导的MAG下调，LPA可显著诱导DR中钙蛋白酶的激活。钙蛋白酶抑制剂预处理可减弱LPA诱导的神经病理性疼痛行为，如痛觉过敏和异常性疼痛。此外，我们发现，坐骨神经损伤激活钙蛋白酶活性在DR中的LPA 1受体依赖性的方式。E-64 d治疗显著阻断神经损伤诱导的MAG下调和神经性疼痛。然而，通过完全弗氏佐剂处理，DR中没有显著的钙蛋白酶激活，并且E-64 d在该炎症模型中未能显示抗痛觉过敏作用。本研究提供了强有力的证据表明，LPA诱导的钙蛋白酶激活通过DR中MAG下调在神经病理性疼痛的表现中起着至关重要的作用。
Lysophosphatidic acid receptor (LPA1) signaling initiates neuropathic pain through demyelination of the dorsal root (DR). Although LPA is found to cause down-regulation of myelin proteins underlying demyelination, the detailed mechanism remains to be determined. In the present study, we found that a single intrathecal (i.t.) injection of LPA evoked a dose- and time-dependent down-regulation of myelin-associated glycoprotein (MAG) in the DR through LPA1 receptor. A similar event was also observed in ex vivo DR cultures. Interestingly, LPA-induced down-regulation of MAG was significantly inhibited by calpain inhibitors (calpain inhibitor X, E-64 and E-64d) and LPA markedly induced calpain activation in the DR. The pre-treatment with calpain inhibitors attenuated LPA-induced neuropathic pain behaviors such as hyperalgesia and allodynia. Moreover, we found that sciatic nerve injury activates calpain activity in the DR in a LPA1 receptor-dependent manner. The E-64d treatments significantly blocked nerve injury-induced MAG down-regulation and neuropathic pain. However, there was no significant calpain activation in the DR by complete Freund’s adjuvant treatment, and E-64d failed to show anti-hyperalgesic effects in this inflammation model. The present study provides strong evidence that LPA-induced calpain activation plays a crucial role in the manifestation of neuropathic pain through MAG down-regulation in the DR.
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DOI：
10.1006/bbrc.1993.1540
发表时间：
1993-05-14
影响因子：
3.1
作者：
PROOST, P;VANDAMME, J;OPDENAKKER, G
通讯作者：
OPDENAKKER, G
影响因子：
4.2
作者：
Fujita, Ryousuke;Kiguchi, Norikazu;Ueda, Hiroshi
通讯作者：
Ueda, Hiroshi
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：
6.2
作者：
OWENS, GC;BUNGE, RP
通讯作者：
BUNGE, RP
影响因子：
13.9
作者：
Costigan M;Scholz J;Woolf CJ
通讯作者：
Woolf CJ