Compartment-specific redox modulation in migraine with aura: a systematic review of context-dependent mechanisms.
5 affiliations
- 1Department of Neurology, The Affiliated Hospital of Yunnan University, 650021 Kunming, Yunnan, China.
- 2School of Clinical Medicine, Kunming Medical University, 650500 Kunming, Yunnan, China.
- 3School of Clinical Medicine, Dali University, 671003 Dali, Yunnan, China.
- 4School of Medicine, University of Electronic Science and Technology of China, 610054 Chengdu, Sichuan, China.
- 5College of Chemical Science and Technology, Yunnan University, 650091 Kunming, Yunnan, China.
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 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.
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BibTeX
@article{li2026compartmentspecific,
title = {{Compartment-specific redox modulation in migraine with aura: a systematic review of context-dependent mechanisms.}},
author = {Fengyu Li and Qishen Duan and Yu Li and Yilang Tian and Lijuan Lu and Xin Xin and Guoliang Zhu and Ying Zhou and Fanyi Kong},
journal = {Journal of oral \& facial pain and headache},
year = {2026},
month = sep,
doi = {10.22514/jofph.2026.059},
url = {https://europepmc.org/article/MED/42895006},
note = {CC BY},
}
RIS
TY - JOUR
TI - Compartment-specific redox modulation in migraine with aura: a systematic review of context-dependent mechanisms.
AU - Fengyu Li
AU - Qishen Duan
AU - Yu Li
AU - Yilang Tian
AU - Lijuan Lu
AU - Xin Xin
AU - Guoliang Zhu
AU - Ying Zhou
AU - Fanyi Kong
PY - 2026
DA - 2026/09/12
JO - Journal of oral & facial pain and headache
DO - 10.22514/jofph.2026.059
UR - https://europepmc.org/article/MED/42895006
AB - 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.
SN - 2333-0384
SN - 2333-0376
ER -