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Polyinosinic\u2010polycytidylic acid (Poly\u2010IC), a TLR3\u2010specific ligand, has shown promise in exerting neuroprotective effects, as it mitigates inflammation in several diseases. Considering that sterile neurogenic inflammation is involved in the pathogenesis of migraine, we explored the impact of Poly\u2010IC on episodic migraine treatment and the potential mechanisms involved.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Episodic migraine was induced in male rats via a single intraperitoneal injection of nitroglycerin. Poly\u2010IC (with or without a TLR3 inhibitor) treatment was performed before migraine induction. Pain was assessed according to the mechanical sensitivity threshold, head\u2010directed grooming, and the Rat Grimace Scale. The expression of TLR3 and its downstream molecule TRIF was subsequently examined, after which calcitonin gene\u2010related peptide (CGRP), c\u2010fos, and proinflammatory cytokine expression was assessed. Moreover, TRIF expression in primary cultured neurons was knocked down by shRNA in\u00a0vitro to further explore the mechanisms by which Poly\u2010IC mediates migraine\u2010like inflammation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Poly\u2010IC treatment significantly upregulated TLR3\/TRIF expression, reduced the production of CGRP, c\u2010fos, and inflammatory cytokines, and alleviated allodynia in an animal model of migraine. Moreover, TRIF knockdown blunted the anti\u2010inflammatory effects of Poly\u2010IC treatment in primary cultured neurons.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Poly\u2010IC exerts therapeutic effects against neurogenic inflammation via the TLR3\/TRIF signaling pathway in an episodic migraine model.<\/jats:p><\/jats:sec>","DOI":"10.1111\/cns.70444","type":"journal-article","created":{"date-parts":[[2025,5,23]],"date-time":"2025-05-23T06:25:44Z","timestamp":1747981544000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Poly\u2010<scp>IC<\/scp> Alleviates Nitroglycerin\u2010Induced Migraine by Inhibiting Neuroinflammation via <scp>TLR3<\/scp>\/<scp>TRIF<\/scp> Signaling Pathway"],"prefix":"10.1111","volume":"31","author":[{"given":"Ye","family":"Hong","sequence":"first","affiliation":[{"name":"Department of Neurology West China Hospital of Sichuan University  Chengdu 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