Poly-IC Alleviates Nitroglycerin-Induced Migraine by Inhibiting Neuroinflammation via TLR3/TRIF Signaling Pathway

Toll-like receptors (TLRs) play critical roles in pain modulation and immune responses. Polyinosinic-polycytidylic acid (Poly-IC), a TLR3-specific 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-IC on episodic migraine treatment and the potential mechanisms involved.

Episodic migraine was induced in male rats via a single intraperitoneal injection of nitroglycerin. Poly-IC (with or without a TLR3 inhibitor) treatment was performed before migraine induction. Pain was assessed according to the mechanical sensitivity threshold, head-directed grooming, and the Rat Grimace Scale. The expression of TLR3 and its downstream molecule TRIF was subsequently examined, after which calcitonin gene-related peptide (CGRP), c-fos, and proinflammatory cytokine expression was assessed. Moreover, TRIF expression in primary cultured neurons was knocked down by shRNA in vitro to further explore the mechanisms by which Poly-IC mediates migraine-like inflammation.

Poly-IC treatment significantly upregulated TLR3/TRIF expression, reduced the production of CGRP, c-fos, and inflammatory cytokines, and alleviated allodynia in an animal model of migraine. Moreover, TRIF knockdown blunted the anti-inflammatory effects of Poly-IC treatment in primary cultured neurons.

Poly-IC exerts therapeutic effects against neurogenic inflammation via the TLR3/TRIF signaling pathway in an episodic migraine model.