Vincristine Regulates C/EBP-β/TGF-β1 to Promote A1 Astrocyte Polarization and Induce Neuropathic Pain.

IF 5.1 2区医学 Q1 CHEMISTRY, MEDICINAL Drug Design, Development and Therapy Pub Date : 2025-02-07 eCollection Date: 2025-01-01 DOI:10.2147/DDDT.S504873

Yunfu Chen, Guangling Tang, Jun Lu, Sijie Tang, Xinglong Xiong, Chao Chen, Lijian Pei, Jing Shi

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Abstract

Background: The neuropathic pain side induced by Vincristine severely limit its clinical application. However, the mechanism of neuropathic pain is not clear. This study aims to clarify the mechanism of C/EBP-β regulating TGF-β1 mediated spinal astrocyte A1/A2 polarization in the neuropathic pain caused by vincristine.

Methods: Neuropathic pain model was established in rats by intraperitoneal injection of Vincristine (VCR). In vitro experiment, the astrocyte model was constructed by Vincristine, and si-C/EBP-β was regulated before VCR administration. Pain threshold of rats was measured by thermal withdrawal latency (TWL) and mechanical withdrawal threshold (MWT), Elisa was used to detect the expression level of inflammatory factors, qRT PCR and Western blotting were used to detect astrocyte polarization markers, C/EBP-β, TGF-β1, p-smad2 and p-smad3.

Results: Following Vincristine administration, the TWL and MWT of rats exhibited a decrease. Additionally, there was an increase in A1 polarization of astrocytes, while A2 polarization remained relatively unchanged. Furthermore, the expression levels of pro-inflammatory factors were elevated, whereas no significant alterations were observed in anti-inflammatory factors. Notably, Vincristine promoted the expression of C/EBP-β and TGF-β1. TGF-β1 inhibitor alleviated VCR induced astrocyte A1 polarization and release of proinflammatory factors, ameliorated abnormal pain. Moreover, silencing C/EBP-β reversed the enhanced expression of TGF-β1 induced by Vincristine, attenuated astrocyte A1 polarization and proinflammatory factor release.

Conclusion: Vincristine induced spinal cord inflammation by promoting A1 polarization of astrocytes via upregulating the C/EBP-β/TGF-β1 signal pathway, thus leading to neuropathic pain. It was different from the traditional signal pathway, this study shown a new signal pathway for astrocyte A1 polarization, which may provide a possibility for clinical treatment of neuropathic pain.

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长春新碱调节C/EBP-β/TGF-β1促进A1星形胶质细胞极化诱导神经性疼痛

背景：长春新碱引起的神经性疼痛严重限制了其临床应用。然而，神经性疼痛的机制尚不清楚。本研究旨在阐明C/EBP-β调控TGF-β1介导的脊髓星形细胞A1/A2极化在长春新碱致神经性疼痛中的作用机制。方法：采用长春新碱（VCR）腹腔注射建立大鼠神经性疼痛模型。体外实验用长春新碱构建星形胶质细胞模型，VCR给药前对si-C/EBP-β进行调控。采用热戒断潜伏期（TWL）和机械戒断阈值（MWT）检测大鼠疼痛阈值，Elisa检测炎症因子表达水平，qRT - PCR和Western blotting检测星形胶质细胞极化标志物C/EBP-β、TGF-β1、p-smad2和p-smad3。结果：长春新碱给药后，大鼠的TWL和MWT均下降。此外，星形胶质细胞A1极化增加，而A2极化相对不变。此外，促炎因子的表达水平升高，而抗炎因子的表达水平无明显变化。长春新碱明显促进C/EBP-β和TGF-β1的表达。TGF-β1抑制剂可减轻VCR诱导的星形胶质细胞A1极化和促炎因子的释放，改善异常疼痛。此外，沉默C/EBP-β可逆转长春新碱诱导的TGF-β1表达增强、星形胶质细胞A1极化和促炎因子释放减弱。结论：长春新碱通过上调C/EBP-β/TGF-β1信号通路，促进星形胶质细胞A1极化，导致神经性疼痛，从而诱导脊髓炎症。与传统的信号通路不同，本研究发现了星形胶质细胞A1极化的新信号通路，为神经性疼痛的临床治疗提供了可能。

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来源期刊

Drug Design, Development and Therapy CHEMISTRY, MEDICINAL-PHARMACOLOGY & PHARMACY

CiteScore

9.00

自引率

0.00%

发文量

382

审稿时长

>12 weeks

期刊介绍： Drug Design, Development and Therapy is an international, peer-reviewed, open access journal that spans the spectrum of drug design, discovery and development through to clinical applications. The journal is characterized by the rapid reporting of high-quality original research, reviews, expert opinions, commentary and clinical studies in all therapeutic areas. Specific topics covered by the journal include: Drug target identification and validation Phenotypic screening and target deconvolution Biochemical analyses of drug targets and their pathways New methods or relevant applications in molecular/drug design and computer-aided drug discovery* Design, synthesis, and biological evaluation of novel biologically active compounds (including diagnostics or chemical probes) Structural or molecular biological studies elucidating molecular recognition processes Fragment-based drug discovery Pharmaceutical/red biotechnology Isolation, structural characterization, (bio)synthesis, bioengineering and pharmacological evaluation of natural products** Distribution, pharmacokinetics and metabolic transformations of drugs or biologically active compounds in drug development Drug delivery and formulation (design and characterization of dosage forms, release mechanisms and in vivo testing) Preclinical development studies Translational animal models Mechanisms of action and signalling pathways Toxicology Gene therapy, cell therapy and immunotherapy Personalized medicine and pharmacogenomics Clinical drug evaluation Patient safety and sustained use of medicines.