The Migraine Attack as a Homeostatic, Neuroprotective Response to Brain Oxidative Stress: Preliminary Evidence for a Theory

• Published in: Headache Vol. 58; no. 1; pp. 118 - 135
• Main Author: Borkum, Jonathan M.
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.01.2018
• Subjects: Animals; Antioxidants; Apoptosis; Brain; Brain - physiopathology; Brain research; Brain-derived neurotrophic factor; Calcitonin; Calcitonin gene-related peptide; Cortex; Cortical spreading depression; Cortical Spreading Depression - physiology; Defensive behavior; Extravasation; Feedback loops; growth factor; Growth factors; Headache; homeostasis; Homeostasis - physiology; Humans; Ion channels; Ischemia; Migraine; Migraine Disorders - pathology; Migraine Disorders - therapy; Mitochondria; Neurogenesis; Neuroprotection; neuroprotective; Neuroprotective Agents - therapeutic use; Nitric oxide; Oxidative stress; Oxidative Stress - physiology; Pain; Peroxides; Platelet Activation; Receptors; regenerative; Serotonin; Substance P; growth factor; homeostasis; migraine; regenerative; neuroprotective; oxidative stress
• ISSN: 0017-8748; 1526-4610
• DOI: 10.1111/head.13214

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.