Targeting Neuronal FKBP5 Attenuates Mechanical Allodynia by Suppressing NF-κB-Mediated Neuroinflammation in an NTG-Induced Chronic Migraine Model
Abstract
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,…
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