CGRP-Uric Acid Axis Proposed as Redox-Inflammatory Framework Linking Neurovascular and Metabolic Regulation in Migraine

Migraine is a complex neurovascular disorder involving intricate interactions between neuronal, vascular, inflammatory, and metabolic processes. Calcitonin gene-related peptide (CGRP) is a well-established key mediator within the trigeminovascular system, playing a crucial role in migraine pathophysiology and serving as a target for recent preventive therapies. While uric acid (UA) is increasingly recognized for its influence on redox balance and inflammatory signaling, its mechanistic link to CGRP in migraine has often been discussed separately. This gap highlights the need for an integrated understanding of how these pathways converge to drive migraine attacks.

This review systematically summarized current evidence regarding CGRP signaling, oxidative stress, and uric acid metabolism to bridge previously disconnected mechanistic discussions. The authors synthesized findings from various studies, including those on CGRP's role in neurovascular function and UA's context-dependent effects on redox and inflammation. Based on this comprehensive synthesis, they proposed a novel, hypothesis-generating CGRP-UA redox-inflammatory framework for migraine, aiming to integrate these distinct but potentially interacting pathways within the trigeminovascular system.

The proposed framework posits that CGRP-associated oxidative stress significantly contributes to neuronal sensitization and neurogenic inflammation in migraine. This oxidative stress acts as a crucial link, connecting neuropeptide activity with downstream immune and metabolic responses. Uric acid demonstrates context-dependent effects: it functions as an extracellular antioxidant by scavenging radicals, breaking lipid peroxidation chains, and chelating metals. Conversely, intracellular accumulation of UA can contribute to oxidative stress and activate the NLRP3 inflammasome.

These intricate pathways appear to converge on shared mediators, including reactive oxygen species (ROS), nuclear factor kappa B (NF-κB), and the NLRP3 inflammasome, suggesting critical interactions within the trigeminovascular system that could drive migraine pathology.