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

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.

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.

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).

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.

CRD420251143073.