Department of Anaesthesiology, University Hospital of Würzburg, Würzburg, Germany.
Wolfson Centre for Age-Related Diseases, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.
Mol Pain. 2020 Jan-Dec;16:1744806920903848. doi: 10.1177/1744806920903848.
High doses of capsaicin are recommended for the treatment of neuropathic pain. However, low doses evoke mechanical hypersensitivity. Activation of the capsaicin chemosensor transient receptor potential vanilloid 1 (TRPV1) induces neurogenic inflammation. In addition to the release of pro-inflammatory mediators, reactive oxygen species are produced. These highly reactive molecules generate oxidised phospholipids and 4-hydroxynonenal (4-HNE) which then directly activate TRP ankyrin 1 (TRPA1). The apolipoprotein A-I mimetic peptide D-4F neutralises oxidised phospholipids. Here, we asked whether D-4F ameliorates neurogenic hypersensitivity in rodents by targeting reactive oxygen species and 4-HNE in the capsaicin-evoked pain model.
Co-application of D-4F ameliorated capsaicin-induced mechanical hypersensitivity and allodynia as well as persistent heat hypersensitivity measured by Randell–Selitto, von Frey and Hargreaves test, respectively. In addition, mechanical hypersensitivity was blocked after co-injection of D-4F with the reactive oxygen species analogue HO or 4-HNE. In vitro studies on dorsal root ganglion neurons and stably transfected cell lines revealed a TRPA1-dependent inhibition of the calcium influx when agonists were pre-incubated with D-4F. The capsaicin-induced calcium influx in TRPV1-expressing cell lines and dorsal root ganglion neurons sustained in the presence of D-4F.
D-4F is a promising compound to ameliorate TRPA1-dependent hypersensitivity during neurogenic inflammation.
高剂量辣椒素被推荐用于治疗神经性疼痛。然而，低剂量会引起机械性过敏。辣椒素化学感受器瞬时受体电位香草酸 1（TRPV1）的激活会引起神经源性炎症。除了释放促炎介质外，还会产生活性氧。这些高反应性分子会产生氧化磷脂和 4-羟基壬烯醛（4-HNE），然后直接激活 TRP 锚蛋白 1（TRPA1）。载脂蛋白 A-I 模拟肽 D-4F 中和氧化磷脂。在这里，我们询问 D-4F 是否通过靶向辣椒素诱发疼痛模型中的活性氧和 4-HNE 来改善啮齿动物的神经性过敏。
D-4F 的共同应用改善了辣椒素引起的机械性过敏和痛觉过敏，以及 Randell–Selitto、von Frey 和 Hargreaves 测试分别测量的持续性热过敏。此外，D-4F 与活性氧类似物 HO 或 4-HNE 共同注射后，机械性过敏被阻断。在背根神经节神经元和稳定转染的细胞系上进行的体外研究表明，当激动剂与 D-4F 预孵育时，会依赖于 TRPA1 抑制钙内流。在存在 D-4F 的情况下，TRPV1 表达细胞系和背根神经节神经元中的辣椒素诱导的钙内流持续存在。
D-4F 是一种有前途的化合物，可以在神经源性炎症期间改善 TRPA1 依赖性过敏。
