Intrathecal 5-azacytidine inhibits global DNA methylation and methyl- CpG-binding protein 2 expression and alleviates neuropathic pain in rats following chronic constriction injury
Intrathecal 5-azacytidine inhibits global DNA methylation and methyl- CpG-binding protein 2 expression and alleviates neuropathic pain in rats following chronic constriction injury
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DOI：
10.1016/j.brainres.2011.08.040
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发表时间：
2011-10-18
期刊：
影响因子：
2.9
通讯作者：
Zou, Wang-Yuan
中科院分区：
文献类型：
--
作者：
Wang, Ying;Liu, Chang;Zou, Wang-Yuan
神经病理性疼痛的发病机制在很大程度上仍不清楚。表观遗传机制可能在调控促伤害或抗伤害感受基因的表达方面发挥重要作用。DNA甲基化是脊椎动物的主要表观遗传学机制，而甲基CpG结合蛋白2(MeCP2)直接参与甲基化介导的基因沉默。为了确定慢性压迫性损伤(CCI)后整体DNA甲基化和MeCP2表达的变化，以及抑制DNA甲基化如何影响这些变化和减轻神经病理性疼痛，我们在CCI大鼠鞘内使用了DNA甲基转移酶抑制剂5-氮胞苷。CCI术后第3天至第14天，每日1次经脊髓注射0.9%生理盐水或5-氮胞苷(10亩·d~(-1))。CCI后第14天，CCI大鼠脊髓整体DNA甲基化和MeCP2表达增加。CCI术后第5天至第14天鞘内注射5-氮杂胞苷可减轻CCI所致的机械性超敏和热痛敏。鞘内注射5-氮胞苷也能显著抑制CCI大鼠脊髓DNA甲基化和MeCP2表达的增加。这些结果表明，神经损伤后脊髓内整体DNA甲基化和MeCP2表达增加可能在神经病理性疼痛中起重要作用。5-氮胞苷显示出治疗神经病理性疼痛的潜力。(C)2011爱思唯尔B.V.保留所有权利。
The pathogenesis of neuropathic pain remains largely unknown. Epigenetic mechanisms may play a major role in regulating expression of pro- or antinociceptive genes. DNA methylation is a major epigenetic mechanism in vertebrates, and methyl- CpG-binding protein 2 (MeCP2) is directly involved in methylation-mediated gene silencing. To determine how changes in global DNA methylation and MeCP2 expression occur following chronic constriction injury (CCI) and how repression of DNA methylation affects these changes and attenuates neuropathic pain, we used intrathecal 5-azacytidine, a DNA methyltransferase inhibitor, in CCI rats. Rats received 0.9% saline or 5-azacytidine (10 mu mol.d(-1)) via spinal injection once daily from day 3 to day 14 after CCI surgery. Global DNA methylation and MeCP2 expression increased in the spinal cord in CCI rats on day 14 after CCI surgery. Mechanical allodynia and thermal hyperalgesia induced by CCI were attenuated by intrathecal 5-azacytidine from day 5 to day 14 after CCI surgery. The increases in global DNA methylation and MeCP2 expression in the spinal cord in CCI rats were also significantly inhibited by intrathecal 5-azacytidine. These results demonstrate that increased global DNA methylation and MeCP2 expression in the spinal cord after nerve damage may play an important role in neuropathic pain. 5-azacytidine shows potential for treating neuropathic pain. (C) 2011 Elsevier B.V. All rights reserved.