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

IF 4.7 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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引用次数: 0

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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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.