毛兰素通过 NLRP3 炎性小体轴预防神经损伤大鼠的 CXCL12/CXCR4 调节性神经病理性疼痛。
Loganin prevents CXCL12/CXCR4-regulated neuropathic pain via the NLRP3 inflammasome axis in nerve-injured rats.
机构信息
Department of Anesthesiology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Anesthesiology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
Department of Pharmacology, Graduate Institute of Medicine, College of Medicine, Drug Development and Value Creation Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan.
出版信息
Phytomedicine. 2021 Nov;92:153734. doi: 10.1016/j.phymed.2021.153734. Epub 2021 Sep 4.
BACKGROUND
Neuropathic pain has been shown to be modulated by the activation of the chemokine C-X-C motif ligand 12 (CXCL12)/chemokine CXC receptor 4 (CXCR4) dependent nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 (NLRP3) inflammasome. Loganin, an iridoid glycoside, was proven to prevent neuropathic pain, but its underlying mechanisms related to NLRP3 activation are still unknown.
PURPOSE
This study investigated the underlying mechanisms of loganin's effect on chronic constriction injury (CCI)-induced NLRP3 inflammasome activation in the spinal cord.
METHODS
Sprague-Dawley rats were randomly divided into four groups: sham, CCI, sham + loganin, and CCI + loganin. Loganin (5 mg/kg/day) was administered intraperitoneally starting the day after surgery. Paw withdrawal threshold (PWT) and latency (PWL) were assessed before CCI and on days 1, 3, 7 and 14 after CCI. Spinal cords were collected for western blots and immunofluorescence studies.
RESULTS
Loganin prevented CCI-attenuated PWT and PWL, suggesting improved mechanical allodynia and thermal hyperalgesia. The expression of CXCL12, CXCR4, thioredoxin-interacting protein (TXNIP), NLRP3 inflammasome (NLRP3, ASC, and caspase-1), IL-1β, and IL-18 were enhanced on day 7 after CCI, and all were reduced after loganin treatment. Dual immunofluorescence also showed that increased CXCL12, CXCR4, and NLRP3 were colocalized with NeuN (neuronal marker), GFAP (astrocyte marker), and Iba1 (microglial marker) on day 7 in the ipsilateral spinal dorsal horn (SDH). These immunoreactivities were attenuated in loganin-treated rats. Moreover, loganin decreased the assembly of NLRP3/ASC inflammasome after CCI in the ipsilateral SDH. Loganin appears to attenuate CCI-induced neuropathic pain by suppressing CXCL12/CXCR4-mediated NLRP3 inflammasome.
CONCLUSION
Our findings suggest that loganin might be a suitable candidate for managing CCI-provoked neuropathic pain.
背景
已证实神经病理性疼痛可通过趋化因子 C-X-C 基序配体 12（CXCL12）/趋化因子 CXC 受体 4（CXCR4）依赖性核苷酸结合寡聚结构域（NOD）样受体蛋白 3（NLRP3）炎性小体的激活来调节。鸡屎藤苷，一种裂环烯醚萜糖苷，已被证明可预防神经病理性疼痛，但与 NLRP3 激活相关的潜在机制尚不清楚。
目的
本研究旨在探讨鸡屎藤苷对慢性压迫性损伤（CCI）诱导的脊髓 NLRP3 炎性小体激活的影响的潜在机制。
方法
将 Sprague-Dawley 大鼠随机分为四组：假手术组、CCI 组、假手术+鸡屎藤苷组和 CCI+鸡屎藤苷组。术后第一天开始每天腹膜内给予鸡屎藤苷（5mg/kg/天）。在 CCI 前和 CCI 后第 1、3、7 和 14 天评估足底撤回阈值（PWT）和潜伏期（PWL）。收集脊髓进行 Western blot 和免疫荧光研究。
结果
鸡屎藤苷可预防 CCI 减弱的 PWT 和 PWL，表明机械性痛觉过敏和热痛觉过敏得到改善。CCI 后第 7 天，CXCL12、CXCR4、硫氧还蛋白相互作用蛋白（TXNIP）、NLRP3 炎性小体（NLRP3、ASC 和半胱天冬酶-1）、IL-1β 和 IL-18 的表达增强，鸡屎藤苷治疗后均降低。双重免疫荧光还显示，在 CCI 后第 7 天，同侧脊髓背角（SDH）中增加的 CXCL12、CXCR4 和 NLRP3 与神经元标志物 NeuN、星形胶质细胞标志物 GFAP 和小胶质细胞标志物 Iba1 共定位。在鸡屎藤苷治疗的大鼠中，这些免疫反应性降低。此外，鸡屎藤苷在同侧 SDH 中降低了 CCI 后 NLRP3/ASC 炎性小体的组装。
鸡屎藤苷似乎通过抑制 CXCL12/CXCR4 介导的 NLRP3 炎性小体来减轻 CCI 诱导的神经病理性疼痛。
结论
我们的研究结果表明，鸡屎藤苷可能是治疗 CCI 引起的神经病理性疼痛的合适候选药物。
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