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Oxidative stress is a plausible unifying principle behind the types of migraine triggers encountered in clinical practice. The possible implications for prevention and for understanding the nature of the migraine attack are discussed.

Background.-Previous research has suggested that migraineurs show higher levels of oxidative stress (lipid peroxides) between migraine attacks and that migraine triggers may further increase brain oxidative stress. Oxidative stress is transduced into a neural signal by the TRPA1 ion channel on meningeal pain receptors, eliciting neurogenic inflammation, a key event in migraine. Thus, migraines may be a response to brain oxidative stress.Results.-In this article, a number of migraine components are considered: cortical spreading depression, platelet activation, plasma protein extravasation, endothelial nitric oxide synthesis, and the release of serotonin, substance P, calcitonin gene-related peptide, and brain-derived neurotrophic factor. Evidence is presented from in vitro research and animal and human studies of ischemia suggesting that each component has neuroprotective functions, decreasing oxidant production, upregulating antioxidant enzymes, stimulating neurogenesis, preventing apoptosis, facilitating mitochondrial biogenesis, and/or releasing growth factors in the brain. Feedback loops between these components are described. Limitations and challenges to the model are discussed.Conclusions.-The theory is presented that migraines are an integrated defensive, neuroprotective response to brain oxidative stress.

Background Calcitonin gene‐related peptide has emerged as a therapeutic target in migraine. Monoclonal antibodies and small molecule receptor antagonists (gepants) directed against CGRP have been approved or are in Phase II or III clinical trials. For monitoring the long‐term safety of these drugs, it is helpful to consider the role of CGRP in brain functioning. Methods Qualitative review of the preclinical literature on CGRP in brain physiology and pathophysiology. Results Within the brain, CGRP is upregulated by stresses such as ischemia, injury, hyperthermia, and seizure, and activates neuroprotective processes. Thus, CGRP buffers intracellular calcium, triggers antiapoptotic signaling, upregulates a number of neurotrophins (including insulin‐like growth factor‐1/IGF‐1, basic fibroblast growth factor/bFGF, and nerve growth factor/NGF), reduces brain edema, and likely increases antioxidant defenses. When released outside the blood‐brain barrier, CGRP likely protects the endothelium, upregulates growth factor signaling from the endothelium to the brain parenchyma, strengthens the blood‐brain barrier, protects the immune privilege of the brain by inhibiting the movement of neutrophils and monocytes, and facilitates neurogenesis and angiogenesis at stem cell niches. Conclusions CGRP participates in a wide range of neuroprotective processes. In theory, migraineurs with comorbid brain pathology might be at increased risk from CGRP inhibition. However, the extent of compensating processes is unknown and will determine whether these risks materialize in practice.

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