NOX4 is an early initiator of neuropathic pain
NOX4 is an early initiator of neuropathic pain
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DOI：
10.1016/j.expneurol.2016.11.008
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发表时间：
2017-02-01
影响因子：
5.3
通讯作者：
Kleinschnitz, Christoph
中科院分区：
文献类型：
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作者：
Geis, Christian;Geuss, Eva;Kleinschnitz, Christoph
神经性疼痛的治疗仍然具有挑战性，因为其病因多种多样且病理机制尚不完全清楚。一种可能的机制是由于非生理性活性氧（ROS）形成而导致的氧化应激。唯一已知的 ROS 专用酶源是 NADPH 氧化酶，其中 4 型异构体 (NOX4) 被认为参与神经病理性疼痛的亚急性和慢性阶段。在这里，我们的目标是通过使用神经性疼痛的慢性压迫性损伤 (CCI) 小鼠模型检查 NOX1/4 特异性抑制剂 GKT136901 的功效，将这一发现转化为治疗策略。出乎意料的是，使用 GKT136901 进行神经损伤后治疗无法有效减少 CCI 后的疼痛相关行为。因此，我们使用独立的 KO 小鼠模型重新研究了 NOX4 的作用。 CCI 后早期，我们发现受损神经中促炎细胞因子、ROS 形成和氧化应激标记物硝基酪氨酸增加，同时 Nox4 基因表达上调。在 NOX4 KO 小鼠中，机械性异常性疼痛从神经损伤后第 4 天开始显着减少，所有 ROS 相关和急性生物标志物也是如此。此外，我们观察到 CCI 诱导的坐骨神经和背根神经节中促炎细胞因子的上调减少以及 NOX4 缺乏。因此，我们得出结论，NOX4 通过在病变部位产生氧化应激和随后的细胞因子失调而参与神经性疼痛状态的发展。这出现在神经损伤后的非常早期阶段，解释了急性后药理 NOX 抑制的无效性。我们建议，NOX4 未来的靶标验证现在应重点关注确定人类神经性疼痛的可能治疗窗口。 (C) 2016 Elsevier Inc. 保留所有权利。
Treatment of neuropathic pain remains challenging as the etiology is heterogeneous and pathomechanisms are incompletely understood. One possible mechanism is oxidative stress due to unphysiological reactive oxygen species (ROS) formation. The only know dedicated enzymatic source of ROS are NADPH oxidases of which the type 4 isoform (NOX4) has been suggested to be involved in the subacute and chronic phase of neuropathic pain. Here, we aim to translate this finding into a treatment strategy by examining the efficacy of the NOX1/4specific inhibitor GKT136901 using the chronic constriction injury (CCI) mouse model of neuropathic pain. Unexpectedly, post-nerve lesion treatment using GKT136901 was ineffective to reduce pain-related behavior after CCI. We therefore re-investigated the role of NOX4 using an independent KO mouse model. Early after CCI we found an increase in pro-inflammatory cytokines, ROS formation and the oxidative stress marker nitrotyrosine in the lesioned nerve together with an upregulated Nox4 gene expression. In NOX4 KO mice, mechanical allodynia was markedly reduced from day 4 after nerve injury as were all ROS related and acute biomarkers. In addition, we observed a reduction in the CCI-induced upregulation of pro-inflammatory cytokines in the sciatic nerve and dorsal root ganglia along with NOX4-deficiency. Thus, we conclude that NOX4 is involved in the development of neuropathic pain states by producing oxidative stress and subsequent cytokine dysregulation at the lesion site. This appears at very early stages immediately after nerve injury explaining ineffectiveness of post-acute pharmacological NOX inhibition. We suggest that future target validation of NOX4 should now focus on defining the possible therapeutic window in human neuropathic pain. (C) 2016 Elsevier Inc. All rights reserved.