Department of Neurobiology and Acupuncture Research, The Third Clinical Medical College, Zhejiang Chinese Medical University, Key Laboratory of Acupuncture and Neurology of Zhejiang Province, 548 Binwen Road, Hangzhou, 310053, China.
J Neuroinflammation. 2021 Feb 18;18(1):48. doi: 10.1186/s12974-021-02098-y.
Paclitaxel is a widely prescribed chemotherapy drug for treating solid tumors. However, paclitaxel-induced peripheral neuropathy (PIPN) is a common adverse effect during paclitaxel treatment, which results in sensory abnormalities and neuropathic pain among patients. Unfortunately, the mechanisms underlying PIPN still remain poorly understood. Long noncoding RNAs (lncRNAs) are novel and promising targets for chronic pain treatment, but their involvement in PIPN still remains unexplored.
We established a rat PIPN model by repetitive paclitaxel application. Immunostaining, RNA sequencing (RNA-Seq) and bioinformatics analysis were performed to study glia cell activation and explore lncRNA/mRNA expression profiles in spinal cord dorsal horn (SCDH) of PIPN model rats. qPCR and protein assay were used for further validation.
PIPN model rats developed long-lasting mechanical and thermal pain hypersensitivities in hind paws, accompanied with astrocyte and microglia activation in SCDH. RNA-Seq identified a total of 814 differentially expressed mRNAs (DEmRNA) (including 467 upregulated and 347 downregulated) and 412 DElncRNAs (including 145 upregulated and 267 downregulated) in SCDH of PIPN model rats vs. control rats. Functional analysis of DEmRNAs and DElncRNAs identified that the most significantly enriched pathways include immune/inflammatory responses and neurotrophin signaling pathways, which are all important mechanisms mediating neuroinflammation, central sensitization, and chronic pain. We further compared our dataset with other published datasets of neuropathic pain and identified a core set of immune response-related genes extensively involved in PIPN and other neuropathic pain conditions. Lastly, a competing RNA network analysis of DElncRNAs and DEmRNAs was performed to identify potential regulatory networks of lncRNAs on mRNA through miRNA sponging.
Our study provided the transcriptome profiling of DElncRNAs and DEmRNAs and uncovered immune and inflammatory responses were predominant biological events in SCDH of the rat PIPN model. Thus, our study may help to identify promising genes or signaling pathways for PIPN therapeutics.
紫杉醇是一种广泛用于治疗实体瘤的化疗药物。然而，紫杉醇引起的周围神经病变（PIPN）是紫杉醇治疗过程中的一种常见不良反应，导致患者出现感觉异常和神经病理性疼痛。不幸的是，PIPN 的发病机制仍知之甚少。长链非编码 RNA（lncRNA）是慢性疼痛治疗的新的有前途的靶点，但它们在 PIPN 中的作用仍未被探索。
我们通过重复应用紫杉醇来建立大鼠 PIPN 模型。通过免疫染色、RNA 测序（RNA-Seq）和生物信息学分析来研究小胶质细胞和星形胶质细胞的激活，并探索 PIPN 模型大鼠脊髓背角（SCDH）中的 lncRNA/mRNA 表达谱。通过 qPCR 和蛋白测定进行进一步验证。
PIPN 模型大鼠的后爪出现了持久的机械性和热痛敏，同时 SCDH 中的星形胶质细胞和小胶质细胞被激活。RNA-Seq 共鉴定出 814 个差异表达的 mRNA（DEmRNA）（包括 467 个上调和 347 个下调）和 412 个差异表达的长链非编码 RNA（DElncRNA）（包括 145 个上调和 267 个下调）在 PIPN 模型大鼠与对照组大鼠的 SCDH 中。DEmRNA 和 DElncRNA 的功能分析表明，最显著富集的途径包括免疫/炎症反应和神经营养素信号通路，这些途径都是介导神经炎症、中枢敏化和慢性疼痛的重要机制。我们进一步将我们的数据集与其他已发表的神经病理性疼痛数据集进行比较，发现了一组广泛涉及 PIPN 和其他神经病理性疼痛的免疫反应相关基因。最后，对 DElncRNA 和 DEmRNA 进行竞争性 RNA 网络分析，通过 miRNA 海绵作用识别 lncRNA 对 mRNA 的潜在调控网络。
我们的研究提供了 DElncRNA 和 DEmRNA 的转录组图谱，并揭示了免疫和炎症反应是大鼠 PIPN 模型 SCDH 中的主要生物学事件。因此，我们的研究可能有助于确定治疗 PIPN 的有前途的基因或信号通路。
