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Background <p>Vestibular migraine (VM) is characterized by recurrent episodes of headache and vertigo, and its pathogenesis is closely associated with neuroinflammation and central sensitization. C-X-C motif chemokine ligand 10 (CXCL10) plays a critical role in neuroinflammation and pain modulation; however, its specific involvement in VM remains unclear.</p> Methods <p>A rat model of VM was established by repeated intraperitoneal nitroglycerin injections combined with intratympanic kainic acid administration. To investigate the role of CXCL10, adeno-associated virus encoding CXCL10-targeted shRNA (CXCL10-shRNA-AAV) was delivered intracerebroventricularly prior to model induction. A rescue experiment was further performed using the PI3K agonist 740 Y-P to reactivate PI3K/AKT signaling. Mechanical pain thresholds (hind paw and periorbital), head scratching and grooming behavior, and vestibular function scores were assessed. Expression levels of CXCL10, CXCR3, PI3K/AKT pathway components, inflammatory cytokines (pro-IL-1β, IL-6, TNF-α), and central sensitization markers (CGRP, c-fos) in the trigeminal nucleus caudalis (TNC) and vestibular nuclei (VN) were examined by Western blot, qPCR, and immunofluorescence.</p> Results <p>VM rats exhibited hyperalgesia, vestibular dysfunction, and upregulated CXCL10 expression in both TNC and VN. Intracerebroventricular delivery of CXCL10-shRNA-AAV effectively knocked down CXCL10 expression and significantly ameliorated pain hypersensitivity and vestibular deficits. Mechanistically, CXCL10 knockdown suppressed PI3K/AKT pathway activation, reduced pro-inflammatory cytokine production (pro-IL-1β, IL-6, TNF-α), and downregulated the central sensitization markers CGRP and c-fos in both TNC and VN. Notably, reactivation of the PI3K/AKT pathway by 740 Y-P partially reversed these effects.</p> Conclusions <p>CXCL10 contributes to VM pathophysiology by activating PI3K/AKT-mediated neuroinflammation and promoting central sensitization. Targeted knockdown of CXCL10 attenuates both pain and vestibular symptoms in a rat VM model, highlighting CXCL10 as a potential novel therapeutic target for VM.</p>

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CXCL10 knockdown attenuates vestibular migraine in rats by inhibiting PI3K-mediated neuroinflammation and central sensitization

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月26日

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  • Mao-mei Song,
  • Gianluca Coppola,
  • Ying-jie Gao,
  • Shi-na Song,
  • Chang-xin Li,
  • Sui-yi Xu

摘要

Background

Vestibular migraine (VM) is characterized by recurrent episodes of headache and vertigo, and its pathogenesis is closely associated with neuroinflammation and central sensitization. C-X-C motif chemokine ligand 10 (CXCL10) plays a critical role in neuroinflammation and pain modulation; however, its specific involvement in VM remains unclear.

Methods

A rat model of VM was established by repeated intraperitoneal nitroglycerin injections combined with intratympanic kainic acid administration. To investigate the role of CXCL10, adeno-associated virus encoding CXCL10-targeted shRNA (CXCL10-shRNA-AAV) was delivered intracerebroventricularly prior to model induction. A rescue experiment was further performed using the PI3K agonist 740 Y-P to reactivate PI3K/AKT signaling. Mechanical pain thresholds (hind paw and periorbital), head scratching and grooming behavior, and vestibular function scores were assessed. Expression levels of CXCL10, CXCR3, PI3K/AKT pathway components, inflammatory cytokines (pro-IL-1β, IL-6, TNF-α), and central sensitization markers (CGRP, c-fos) in the trigeminal nucleus caudalis (TNC) and vestibular nuclei (VN) were examined by Western blot, qPCR, and immunofluorescence.

Results

VM rats exhibited hyperalgesia, vestibular dysfunction, and upregulated CXCL10 expression in both TNC and VN. Intracerebroventricular delivery of CXCL10-shRNA-AAV effectively knocked down CXCL10 expression and significantly ameliorated pain hypersensitivity and vestibular deficits. Mechanistically, CXCL10 knockdown suppressed PI3K/AKT pathway activation, reduced pro-inflammatory cytokine production (pro-IL-1β, IL-6, TNF-α), and downregulated the central sensitization markers CGRP and c-fos in both TNC and VN. Notably, reactivation of the PI3K/AKT pathway by 740 Y-P partially reversed these effects.

Conclusions

CXCL10 contributes to VM pathophysiology by activating PI3K/AKT-mediated neuroinflammation and promoting central sensitization. Targeted knockdown of CXCL10 attenuates both pain and vestibular symptoms in a rat VM model, highlighting CXCL10 as a potential novel therapeutic target for VM.