Work

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

Year: 2026

Type: article

Abstract: Background Chronic migraine is a debilitating neurological disorder characterized by trigeminovascular sensitization and neuroinflammation. While FK506-binding protein 51 (FKBP5) modulates spinal neuroinflammation in chronic pain, its specific role in trigeminovascular nociceptive processing and chronic migraine pathogenesis remains largely unknown. Methods We utilized a nitroglycerin (NTG)-induced chronic migraine mouse model. Following RNA-sequencing (RNA-seq) of the trigeminal nucleus caudalis (TNC), target expression was validated via quantitative reverse transcription-PCR (RT-qPCR), Western blotting, and immunofluorescence. To establish causality, we employed a neuron-specific CRISPR-Cas9 editing system for Fkbp5 knockout within the TNC, alongside pharmacological interventions using the specific FKBP5 antagonist SAFit2 and the 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, and Western blotting 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 (IL-1β, IL-6, and TNF-α) and the upregulation of 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 identified neuronal FKBP5 as a critical driver of chronic migraine pathogenesis. FKBP5 sustains mechanical allodynia by activating the NF-κB-mediated neuroinflammatory cascade. Consequently, targeting FKBP5 represents a promising therapeutic strategy for chronic migraine.

Source: The Journal of Headache and Pain

DOI: 10.1186/s10194-026-02460-6