Nanomedicine-driven neuropathic pain relief in a rat model is associated with macrophage polarity and mast cell activation
Nanomedicine-driven neuropathic pain relief in a rat model is associated with macrophage polarity and mast cell activation
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DOI：
10.1186/s40478-019-0762-y
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发表时间：
2019-07-05
影响因子：
7.1
通讯作者：
Pollock, John A.
中科院分区：
文献类型：
--
作者：
Saleem, Muzamil;Deal, Brooke;Pollock, John A.
我们探索了免疫神经病理学基础的神经性疼痛在大鼠模型中的坐骨神经开始，通过使用纳米乳液为基础的纳米药物作为生物探针的多日缓解。纳米医学是治疗诊断学：治疗（含有塞来昔布药物）和诊断（含有近红外荧光（NIRF）染料），并且足够小以被循环单核细胞吞噬。我们发现，疼痛样行为在术后8天达到最大超敏反应的平台期，这是在这个时间点静脉给药的基本原理。疼痛在24小时内明显缓解，持续约6天。通过免疫荧光和共聚焦显微镜在疼痛缓解的峰值（手术后第12天）和疼痛样超敏反应恢复时（手术后第18天）研究纳米药物和对照（无药物的纳米乳液）治疗的动物的同侧坐骨神经和相关的L4和L5背根神经节（DRG）组织。在第12天，治疗后在坐骨神经处观察到浸润性巨噬细胞、肥大细胞和肥大细胞脱粒显著减少。在DRG中，在第12天和第18天均无给药效应。相反，在DRG，在第18天巨噬细胞浸润和肥大细胞脱粒显著增加。通过评估巨噬细胞环氧合酶-2（考克斯-2）（药物靶点）和细胞外前列腺素E2（PGE 2）的表达以及M1（促炎）和M2（抗炎）巨噬细胞的比例，进一步研究了对坐骨神经中免疫病理学的治疗效果。在第12天，考克斯-2阳性巨噬细胞、细胞外PGE 2显著减少，巨噬细胞极性显著逆转。在第18天，这些测量值恢复到对照给药动物中观察到的水平。在这里，我们提出了一种新的免疫神经病理学研究范式，通过采用纳米医学来靶向神经性疼痛的机制，从而导致持久的疼痛缓解，同时揭示了受损神经和相关DRG的新型免疫病理学。
We explored the immune neuropathology underlying multi-day relief from neuropathic pain in a rat model initiated at the sciatic nerve, by using a nanoemulsion-based nanomedicine as a biological probe. The nanomedicine is theranostic: both therapeutic (containing celecoxib drug) and diagnostic (containing near-infrared fluorescent (NIRF) dye) and is small enough to be phagocytosed by circulating monocytes. We show that pain-like behavior reaches a plateau of maximum hypersensitivity 8days post-surgery, and is the rationale for intravenous delivery at this time-point. Pain relief is evident within 24h, lasting approximately 6days. The ipsilateral sciatic nerve and associated L4 and L5 dorsal root ganglia (DRG) tissue of both nanomedicine and control (nanoemulsion without drug) treated animals was investigated by immunofluorescence and confocal microscopy at the peak of pain relief (day-12 post-surgery), and when pain-like hypersensitivity returns (day-18 post-surgery). At day-12, a significant reduction of infiltrating macrophages, mast cells and mast cell degranulation was observed at the sciatic nerve following treatment. In the DRG, there was no effect of treatment at both day-12 and day-18. Conversely, at the DRG, there is a significant increase in macrophage infiltration and mast cell degranulation at day-18. The treatment effect on immune pathology in the sciatic nerve was investigated further by assessing the expression of macrophage cyclooxygenase-2 (COX-2)-the drug target-and extracellular prostaglandin E2 (PGE2), as well as the proportion of M1 (pro-inflammatory) and M2 (anti-inflammatory) macrophages. At day-12, there is a significant reduction of COX-2 positive macrophages, extracellular PGE2, and a striking reversal of macrophage polarity. At day-18, these measures revert to levels observed in control-treated animals. Here we present a new paradigm of immune neuropathology research, by employing a nanomedicine to target a mechanism of neuropathic pain-resulting in long-lasting pain relief--whilst revealing novel immune pathology at the injured nerve and associated DRG.