Redox Mechanisms in Migraine: Novel Therapeutics and Dietary Interventions

Significance: Migraine represents the third most prevalent and the seventh most disabling human disorder. Approximately 30% of migraine patients experience transient, fully reversible, focal neurological symptoms (aura) preceding the attack. Recent Advances: Awareness of the hypothesis that migraine actually embodies a spectrum of illnesses—ranging from episodic to chronic forms—is progressively increasing and poses novel challenges for clarifying the underlying pathophysiological mechanisms of migraine as well as for the development of novel therapeutic interventions. Several theories have evolved to the current concept that a combination of genetic, epigenetic, and environmental factors may play a role in migraine pathogenesis, although their relative importance is still being debated. Critical Issues: One critical issue that deserves a particular attention is the role of oxidative stress in migraine. Indeed, potentially harmful oxidative events occur during the migraine attack and long-lasting or frequent migraine episodes may increase brain exposure to oxidative events that can lead to chronic transformation. Moreover, a wide variety of dietary, environmental, physiological, behavioral, and pharmacological migraine triggers may act through oxidative stress, with clear implications for migraine treatment and prophylaxis. Interestingly, almost all current prophylactic migraine agents exert antioxidant effects. Future Directions: Increasing awareness of the role of oxidative stress and/or decreased antioxidant defenses in migraine pathogenesis and progression to a chronic condition lays the foundations for the design of novel prophylactic approaches, which, by reducing brain oxidative phenomena, could favorably modify the clinical course of migraine. Antioxid. Redox Signal. 28, 1144–1183. I. Introduction A. Migraine epidemiology 1. Incidence 2. Prevalence 3. Risk factors B. Pathophysiology of migraine 1. Cortical spreading depression 2. Neurogenic inflammation II. Oxidative Stress in Migraine A. Redox mechanisms in the brain 1. Reactive nitrogen oxide species generating systems 2. Antioxidant mechanisms B. Mediators of inflammation and oxidative stress in migraine 1. Calcitonin gene-related peptide 2. Nitric oxide 3. Transient receptor potential channels 4. Substance P 5. Neurokinin A C. Oxidative triggers of migraine 1. Dietary aspects 2. Environmental aspects 3. Physiological aspects 4. Behavioral aspects 5. Pharmacological aspects III. Molecular Features of Oxidative Stress in Migraine A. Redox gene polymorphisms and migraine 1. SODs and CAT 2. Nitric oxide synthases 3. Prion protein 4. Paraoxonase 1 5. APOE gene 6. Lipoprotein-associated phospholipase A2 7. Other oxidative stress-related gene polymorphisms B. Genome-wide association studies in migraine IV. Oxidative Stress, Hypercoagulability, and Vascular Risk in Migraine A. Oxidative stress and the hemostatic system 1. Effects on coagulation activation 2. Effects on platelet activation B. Oxidative stress and thrombophilia in migraine V. Antioxidant Properties of Current Acute and Preventive Migraine Treatments VI. Novel Therapeutics and Dietary Interventions in Migraine A. Novel therapeutic targets 1. New drugs targeting the CGRP system a. Small molecule CGRP-RAs b. Monoclonal antibodies 2. Nitric oxide inhibitors a. Acute migraine treatment b. Migraine prophylaxis 3. Pituitary adenylate cyclase-activating peptide 4. Orexins 5. Vasoactive intestinal polypeptide B. Nutritional approaches to migraine 1. Is migraine a diet-related disorder? 2. KD in migraine 3. Dietary supplementation with natural products in migraine VII. Conclusions and Future Directions