Scholarlink

Background <p>Chronic migraine (CM) is a debilitating neurological disorder characterized by persistent trigeminovascular sensitization and neuroinflammation. While FK506-binding protein 51 (FKBP5) modulates spinal neuroinflammation in chronic pain, its specific role in trigeminovascular nociceptive processing and CM pathogenesis remains largely unknown.</p> Methods <p>We used a nitroglycerin (NTG)-induced CM mouse model. Following RNA-sequencing (RNA-seq) of total RNA isolated from trigeminal nucleus caudalis (TNC) tissue lysates, target expression was validated via reverse transcription quantitative PCR (RT-qPCR), Western blotting, and immunofluorescence. To establish causality, we used a neuron-specific CRISPR-Cas9 editing system for <i>Fkbp5</i> knockout within the TNC, alongside pharmacological interventions using the specific FKBP5 antagonist SAFit2 and the nuclear factor kappa B (NF-κB) inhibitor PDTC. Migraine-like behaviors were evaluated using von Frey filaments, coupled with biochemical analyses of NF-κB cascade activation and trigeminovascular neuroinflammation.</p> Results <p>RNA-seq, RT-qPCR, Western blotting, and immunofluorescence consistently confirmed a marked upregulation of <i>Fkbp5</i> mRNA and FKBP5 protein in the TNC of NTG-treated mice, predominantly localized to neurons. Concurrently, significant microglial and astrocytic activation was observed in the TNC. Both neuron-specific <i>Fkbp5</i> knockout and pharmacological inhibition with SAFit2 significantly attenuated NTG-induced periorbital and hind paw mechanical allodynia. Furthermore, FKBP5 deficiency blunted the NTG-triggered phosphorylation of p65 and IκBα, effectively suppressing the downstream release of pro-inflammatory cytokines, including interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α), as well as the upregulation of calcitonin gene-related peptide (CGRP) and c-Fos. Crucially, targeted blockade of the NF-κB cascade with PDTC recapitulated the protective behavioral and biochemical effects of FKBP5 deficiency.</p> Conclusions <p>We demonstrate that neuronal FKBP5 is significantly associated with CM pathogenesis. FKBP5 sustains mechanical allodynia by activating the NF-κB-mediated neuroinflammatory cascade. Consequently, targeting FKBP5 represents a promising therapeutic strategy for CM.</p> Graphical abstract <p></p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Targeting neuronal FKBP5 attenuates mechanical allodynia by suppressing NF-κB-mediated neuroinflammation in an NTG-induced chronic migraine mouse model

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年7月22日

查看全文
  • Cheng Peng,
  • Tianhua Fan,
  • Gang Zhou,
  • Min Zhao,
  • Tianxiao Wang,
  • Tingting Cao,
  • Jingyuan Zheng,
  • Zijuan Guo,
  • Guining Liang,
  • Zhenchang Zhang,
  • Ji-Song Guan,
  • Yonggang Wang

摘要

Background

Chronic migraine (CM) is a debilitating neurological disorder characterized by persistent trigeminovascular sensitization and neuroinflammation. While FK506-binding protein 51 (FKBP5) modulates spinal neuroinflammation in chronic pain, its specific role in trigeminovascular nociceptive processing and CM pathogenesis remains largely unknown.

Methods

We used a nitroglycerin (NTG)-induced CM mouse model. Following RNA-sequencing (RNA-seq) of total RNA isolated from trigeminal nucleus caudalis (TNC) tissue lysates, target expression was validated via reverse transcription quantitative PCR (RT-qPCR), Western blotting, and immunofluorescence. To establish causality, we used a neuron-specific CRISPR-Cas9 editing system for Fkbp5 knockout within the TNC, alongside pharmacological interventions using the specific FKBP5 antagonist SAFit2 and the nuclear factor kappa B (NF-κB) inhibitor PDTC. Migraine-like behaviors were evaluated using von Frey filaments, coupled with biochemical analyses of NF-κB cascade activation and trigeminovascular neuroinflammation.

Results

RNA-seq, RT-qPCR, Western blotting, and immunofluorescence consistently confirmed a marked upregulation of Fkbp5 mRNA and FKBP5 protein in the TNC of NTG-treated mice, predominantly localized to neurons. Concurrently, significant microglial and astrocytic activation was observed in the TNC. Both neuron-specific Fkbp5 knockout and pharmacological inhibition with SAFit2 significantly attenuated NTG-induced periorbital and hind paw mechanical allodynia. Furthermore, FKBP5 deficiency blunted the NTG-triggered phosphorylation of p65 and IκBα, effectively suppressing the downstream release of pro-inflammatory cytokines, including interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α), as well as the upregulation of calcitonin gene-related peptide (CGRP) and c-Fos. Crucially, targeted blockade of the NF-κB cascade with PDTC recapitulated the protective behavioral and biochemical effects of FKBP5 deficiency.

Conclusions

We demonstrate that neuronal FKBP5 is significantly associated with CM pathogenesis. FKBP5 sustains mechanical allodynia by activating the NF-κB-mediated neuroinflammatory cascade. Consequently, targeting FKBP5 represents a promising therapeutic strategy for CM.

Graphical abstract