Tang Yidan, Liu Changliang, Zhu Tao, Chen Hai, Sun Yalan, Zhang Xueying, Zhao Qi, Wu Jiahui, Fei Xuejie, Ye Shixin, Chen Chan
Department of Anesthesiology and National Clinical Research Center for Geriatrics, Laboratory of Anesthesia and Critical Care Medicine, Translational Neuroscience Center, West China Hospital, The Research Units of West China, Chinese Academy of Medical Science, Sichuan University, Chengdu, China.
Precision Medicine Research Center, West China Hospital, Sichuan University, Chengdu, China.
Front Cell Dev Biol. 2022 Apr 25;10:843297. doi: 10.3389/fcell.2022.843297. eCollection 2022.
Chronic neuropathic pain is commonly associated with memory loss, which increases the risk of dementia, lowers life quality and spending. On the other hand, the molecular processes are unknown, and effective therapies have yet to be discovered. Long non-coding RNAs (lncRNAs) are emerging potential therapeutic targets for chronic pain, but their role in chronic pain-induced memory impairment is unknown. We established a CCI-induced memory impairment rat model. To investigate and validate the gene expression alterations in the hippocampus of CCI-induced memory impairment, we used RNA-Seq, bioinformatics analysis, qRT-PCR, western blot, immunostaining, Nissl staining, and Diaminobenzidine-enhanced Perls' stain. CCI rats displayed long-term memory deficits in the Y maze and novel objective recognition tests, and chronic mechanical and thermal pain hypersensitivity in the hind paws. We found a total of 179 differentially expressed mRNAs (DEmRNAs) (81 downregulated and 98 upregulated) and 191 differentially expressed long noncoding RNAs (DElncRNAs) (87 downregulated and 105 upregulated) between the hippocampus CA1 of CCI-induced memory impairment model and the sham control, using RNA-Seq expression profiles. The most enriched pathways involving oxidation and iron metabolism were explored using a route and function pathway analysis of DEmRNAs and DElncRNAs. We also discovered that ATF3 was considerably overexpressed in the hippocampal CA1 area, and gene markers of ferroptosis, such as GPX4, SLC7A11, SLC1A5, and PTGS2, were dysregulated in the CCI-induced memory impairment paradigm. Furthermore, in the hippocampus CA1 of CCI-induced memory impairment, lipid peroxidation and iron overload were considerably enhanced. Fer-1 treatment reversed ferroptosis damage of CCI with memory impairment model. Finally, in CCI-induced memory impairment, a competing RNA network analysis of DElncRNAs and DEmRNAs was performed to investigate the putative regulatory link of DElncRNAs on DEmRNAs via miRNA sponging. Using RNA-Seq, we created a genome-wide profile of the whole hippocampus of a rat model of CCI-induced memory impairment. In the hippocampus, pathways and function analyses revealed numerous intriguing genes and pathways involved in ferroptosis and memory impairment in response to chronic pain stress. As a result, our research may aid in the identification of potential and effective treatments for CCI-induced memory impairment.
慢性神经性疼痛通常与记忆丧失有关，这会增加患痴呆症的风险，降低生活质量并增加开支。另一方面，其分子机制尚不清楚，有效的治疗方法也有待发现。长链非编码RNA（lncRNAs）正成为慢性疼痛潜在的治疗靶点，但其在慢性疼痛引起的记忆障碍中的作用尚不清楚。我们建立了一种CCI诱导的记忆障碍大鼠模型。为了研究和验证CCI诱导的记忆障碍大鼠海马体中的基因表达变化，我们使用了RNA测序、生物信息学分析、qRT-PCR、蛋白质免疫印迹、免疫染色、尼氏染色和二氨基联苯胺增强的普鲁士蓝染色。CCI大鼠在Y迷宫和新物体识别测试中表现出长期记忆缺陷，后爪出现慢性机械性和热痛超敏反应。通过RNA测序表达谱，我们发现CCI诱导的记忆障碍模型海马体CA1区与假手术对照组之间共有179个差异表达的mRNA（DEmRNAs）（81个下调，98个上调）和191个差异表达的长链非编码RNA（DElncRNAs）（87个下调，105个上调）。通过对DEmRNAs和DElncRNAs进行通路和功能通路分析，探索了最富集的涉及氧化和铁代谢的通路。我们还发现，ATF3在海马体CA1区显著过表达，并且在CCI诱导的记忆障碍模型中，铁死亡的基因标志物如GPX4、SLC7A11、SLC1A5和PTGS2表达失调。此外，在CCI诱导的记忆障碍模型的海马体CA1区，脂质过氧化和铁过载显著增强。Fer-1治疗逆转了CCI诱导的记忆障碍模型的铁死亡损伤。最后，在CCI诱导的记忆障碍模型中，对DElncRNAs和DEmRNAs进行竞争性RNA网络分析，以研究DElncRNAs通过miRNA海绵作用对DEmRNAs的潜在调控联系。通过RNA测序，我们创建了CCI诱导的记忆障碍大鼠模型整个海马体的全基因组图谱。在海马体中，通路和功能分析揭示了许多与铁死亡和慢性疼痛应激引起的记忆障碍相关的有趣基因和通路。因此，我们的研究可能有助于识别针对CCI诱导的记忆障碍的潜在有效治疗方法。
