Compartment-specific redox modulation in migraine with aura: a systematic review of context-dependent mechanisms
Abstract
Background: Preventive therapies for migraine with aura (MA) remain suboptimal, with 37–54% of patients failing to achieve a >50% reduction in migraine days despite calcitonin gene-related peptide (CGRP)-targeted therapies, while broad-spectrum antioxidants show inconsistent benefits. This gap suggests that indiscriminate reactive oxygen species (ROS) scavenging is insufficient, but emerging evidence indicates that ROS function as compartment-specific signaling molecules rather than uniform toxins. Whether this compartment-specific redox modulation occurs within the cortical spreading depression (CSD) cascade and contributes to the limited efficacy of antioxidant therapies remains unclear. We synthesized preclinical evidence to characterize CSD–redox interactions and identify the translational gap limiting precision strategies for MA. Methods: We systematically searched five databases through June 2025 following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines. Risk of bias was assessed using the Systematic Review Centre for Laboratory Animal Experimentation (SYRCLE) risk-of-bias tool. Given the anticipated heterogeneity, a qualitative synthesis was conducted. Results: Thirteen studies (594 animals, 85% male) were included. CSD-evoked ROS were associated with transient receptor potential ankyrin 1 (TRPA1)/CGRP signaling and oxidative wavefront propagation. Under bioenergetic stress, ROS accumulation was associated with metabolic…
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Evidence Hub reads this as a systematic review. Its evidence level is 1 of 5 (Highest · pooled evidence). Pooled evidence from several studies sits at the top of the evidence pyramid.
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