N-acetyl-cysteine attenuates neuropathic pain by suppressing matrix metalloproteinases
N-acetyl-cysteine attenuates neuropathic pain by suppressing matrix metalloproteinases
复制标题
N-乙酰半胱氨酸通过抑制基质金属蛋白酶来减轻神经性疼痛。
DOI：
10.1097/j.pain.0000000000000575
复制
发表时间：
2016-08-01
期刊：
影响因子：
7.4
通讯作者：
Liu, Wentao
中科院分区：
文献类型：
--
作者：
Li, Jiajie;Xu, Lujie;Liu, Wentao
神经性疼痛的治疗仍然是一个临床挑战，因为它的机制不清楚和广泛的临床发病率。基质金属蛋白酶(MMP)-9和MMP-2先前被描述为神经性疼痛的关键成分，因为它们促进炎症细胞因子成熟和诱导神经炎症。因此，抑制MMPs可能是治疗神经性疼痛的一种新的治疗方法。在这项研究中，我们报道了n -乙酰半胱氨酸（NAC）是一种广泛使用的呼吸系统药物，通过一种独特的MMP抑制机制显著减轻神经性疼痛。NAC在体外（0.1 mM）和体内均显著抑制了MMP-9/2的活性。口服NAC（50、100和200 mg/kg）不仅可以延缓大鼠慢性收缩性损伤（CCI）引起的神经性疼痛的发生，而且可以抑制其维持。NAC阻断了白细胞介素-1 β的成熟，而白细胞介素-1 β是MMPs的关键底物，并显著抑制CCI诱导的神经元活化，包括抑制蛋白激酶C γ、NMDAR1和丝裂原活化蛋白激酶的磷酸化。最后，NAC显著抑制cci诱导的小胶质细胞活化，但对星形胶质细胞无显著影响。这些结果证明了一种有效和安全的方法，已被临床用于通过抑制MMPs的激活来减轻神经性疼痛。
The treatment of neuropathic pain remains a clinical challenge because of its unclear mechanisms and broad clinical morbidity. Matrix metalloproteinase (MMP)-9 and MMP-2 have previously been described as key components in neuropathic pain because of their facilitation of inflammatory cytokine maturation and induction of neural inflammation. Therefore, the inhibition of MMPs may represent a novel therapeutic approach to the treatment of neuropathic pain. In this study, we report that N-acetyl-cysteine (NAC), which is a broadly used respiratory drug, significantly attenuates neuropathic pain through a unique mechanism of MMP inhibition. Both the in vitro (0.1 mM) and in vivo application of NAC significantly suppressed the activity of MMP-9/2. Orally administered NAC (50, 100, and 200 mg/kg) not only postponed the occurrence but also inhibited the maintenance of chronic constrictive injury (CCI)induced neuropathic pain in rats. The administration of NAC blocked the maturation of interleukin-1 beta, which is a critical substrate of MMPs, and markedly suppressed the neuronal activation induced by CCI, including inhibiting the phosphorylation of protein kinase C gamma, NMDAR1, and mitogen-activated protein kinases. Finally, NAC significantly inhibited CCI-induced microglia activation but elicited no notable effects on astrocytes. These results demonstrate an effective and safe approach that has been used clinically to alleviate neuropathic pain through the powerful inhibition of the activation of MMPs.