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

Abstract

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.

Headache Triggers as Surprise

“…This model postulates that trigger factors all increase oxidative stress, either directly or indirectly, and the physiological response to this stress initiates a migraine attack. Borkum credits observations of Blau and Benemi in that migraine triggers can be uniformly characterized by their oxidative challenges to the brain and that migraine attacks are a defensive response to such challenges . A third model proposed by Burstein and Jakubowski organizes headache triggers by their inputs to the central nervous system .…”

“…In this model, virtually anything can be conditioned to be a trigger, but careful exposure to the trigger extinguishes the fear response and corresponding potency of the trigger . Borkum has expounded a very different model based on oxidative stress . This model postulates that trigger factors all increase oxidative stress, either directly or indirectly, and the physiological response to this stress initiates a migraine attack.…”

“…11,12 Borkum has expounded a very different model based on oxidative stress. 14,15 This model postulates that trigger factors all increase oxidative stress, either directly or indirectly, and the physiological response to this stress initiates a migraine attack. Borkum credits observations of Blau 16 and Benemi 17 in that migraine triggers can be uniformly characterized by their oxidative challenges to the brain and that migraine attacks are a defensive response to such challenges.…”

“…Borkum credits observations of Blau 16 and Benemi 17 in that migraine triggers can be uniformly characterized by their oxidative challenges to the brain and that migraine attacks are a defensive response to such challenges. 15 A third model proposed by Burstein and Jakubowski organizes headache triggers by their inputs to the central nervous system. 18 This model proposes that the diverse set of triggers activates a correspondingly diverse set of brain regions, but these regions all share projections to the superior salivatory nucleus.…”

CGRP and Brain Functioning: Cautions for Migraine Treatment

“…Implicit in the choice of CGRP as a therapeutic target in migraine is the assumption that the migraine attack is a disorder to which treatment should be directed. An alternative possibility is that the attack is a physiologic response to threats to the brain, serving to restore homeostasis …”