Targeted cyclooxygenase-2 inhibiting nanomedicine results in pain-relief and differential expression of the RNA transcriptome in the dorsal root ganglia of injured male rats.
Targeted cyclooxygenase-2 inhibiting nanomedicine results in pain-relief and differential expression of the RNA transcriptome in the dorsal root ganglia of injured male rats.
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DOI：
10.1177/1744806920943309
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发表时间：
2020-01
期刊：
影响因子：
3.3
通讯作者：
Pollock JA
中科院分区：
文献类型：
--
作者：
Stevens AM;Saleem M;Deal B;Janjic J;Pollock JA
大鼠坐骨神经的慢性压迫性损伤引起周围神经病变，导致人类常见的疼痛样行为。神经病是神经性疼痛的主要原因，其涉及外周神经系统中复杂的细胞和分子反应，神经元、神经胶质和浸润免疫细胞之间相互作用。在这项研究中，我们利用非甾体类抗炎药纳米乳剂将环氧合酶-2抑制剂塞来昔布直接递送至神经损伤后的循环单核细胞，这提供了持久的疼痛缓解。然而，目前还不完全清楚环氧化酶-2抑制在巨噬细胞旅行到损伤部位影响背根神经节中的基因表达。为了阐明慢性压迫性损伤中疼痛样行为的分子机制，以及随后的治疗疼痛缓解，我们采用了与大鼠坐骨神经损伤相关的背根神经节的RNAseq转录组分析。以这种方式使用高通量RNA测序提供了对参与这种神经炎症反应的分子机制的深入了解。我们比较了以下研究组的背根神经节的转录组：给予环氧合酶-2抑制性塞来昔布负载纳米乳剂的慢性压迫性损伤动物，给予溶媒治疗、无药物纳米乳剂的慢性压迫性损伤动物，以及一组未经处理、未手术和未治疗的大鼠。结果显示115个基因的广泛差异表达。利用蛋白质注释通过进化关系分类系统，我们已经揭示了疼痛相关的信号通路和神经炎症反应的潜在生物学机制。定量聚合酶链反应验证证实了几个基因的表达变化。这项研究表明，通过直接抑制损伤坐骨神经浸润巨噬细胞中的环氧合酶-2活性，背根神经节细胞体中的转录组发生相关变化。
Chronic constriction injury of the sciatic nerve in rats causes peripheral neuropathy leading to pain-like behaviors commonly seen in humans. Neuropathy is a leading cause of neuropathic pain, which involves a complex cellular and molecular response in the peripheral nervous system with interactions between neurons, glia, and infiltrating immune cells. In this study, we utilize a nonsteroidal anti-inflammatory drug -loaded nanoemulsion to deliver the cyclooxygenase-2 inhibitor, Celecoxib, directly to circulating monocytes following nerve injury, which provides long-lasting pain relief. However, it is not fully understood how cyclooxygenase-2 inhibition in a macrophage traveling to the site of injury impacts gene expression in the dorsal root ganglia. To elucidate aspects of the molecular mechanisms underlying pain-like behavior in chronic constriction injury, as well as subsequent pain relief with treatment, we employ RNAseq transcriptome profiling of the dorsal root ganglia associated with the injured sciatic nerve in rats. Using high throughput RNA sequencing in this way provides insight into the molecular mechanisms involved in this neuroinflammatory response. We compare the transcriptome from the dorsal root ganglias of the following study groups: chronic constriction injury animals administered with cyclooxygenase-2 inhibiting celecoxib-loaded nanoemulsion, chronic constriction injury animals administered with vehicle treatment, a drug-free nanoemulsion, and a group of naïve, unoperated and untreated rats. The results show an extensive differential expression of 115 genes. Using the protein annotation through evolutionary relationship classification system, we have revealed pain-related signaling pathways and underlying biological mechanisms involved in the neuroinflammatory response. Quantitative polymerase chain reaction validation confirms expression changes for several genes. This study shows that by directly inhibiting cyclooxygenase-2 activity in infiltrating macrophages at the injured sciatic nerve, there is an associated change in the transcriptome in the cell bodies of the dorsal root ganglia.
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影响因子：
7.3
作者：
Freichel M;Almering J;Tsvilovskyy V
通讯作者：
Tsvilovskyy V
影响因子：
3.3
作者：
Janjic JM;Vasudeva K;Saleem M;Stevens A;Liu L;Patel S;Pollock JA
通讯作者：
Pollock JA
影响因子：
1.2
作者：
Saleem, Muzamil;Stevens, Andrea M.;Pollock, John A.
通讯作者：
Pollock, John A.
影响因子：
13.9
作者：
Costigan M;Scholz J;Woolf CJ
通讯作者：
Woolf CJ
神经炎症驱动的慢性疼痛的新兴目标。
影响因子：
120.1
作者：
Ji, Ru-Rong;Xu, Zhen-Zhong;Gao, Yong-Jing
通讯作者：
Gao, Yong-Jing