Compartment-specific redox modulation in migraine with aura: a systematic review of context-dependent mechanisms

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 collapse, which may trigger CSD onset. Microglial M1-like polarization was associated with reduced CSD thresholds. High-dose melatonin accelerated CSD propagation without improving oxidative markers, suggesting limitations of global antioxidant strategies rather than invalidation of the redox framework. Cell-specific protective mechanisms emerged through microglial M2a-like polarization and compartment-specific stabilization of insulin-like growth factor-1 (IGF-1). Conclusion: CSD–redox interactions represent a context-dependent reciprocal axis. Clinical failure of broad-spectrum scavengers may reflect disruption of oxidative eustress. Modulators of microglial M2a-like phenotype and compartment-specific bioenergetic stabilizers should be prioritized for future drug development. Intranasal IGF-1 represents a potentially translatable strategy for attenuating trigeminal CGRP release and oxidative markers, although this requires validation in female cohorts and assessment of sex-specific effects. The PROSPERO Registration: CRD420251143073.

Migraine with aura; Cortical spreading depression; Oxidative stress; Microglial polarization; Redox targeting; Systematic review

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