“I am suggesting that headache—the kind that does not derive from disease or trauma—is a major response that serves to protect the brain from being overtaxed and put out of order”—John R. Graham, 1988: Migraine, Quo Vadis? [1]
Abstract
People with migraine are prone to a brain energy deficit between attacks, through increased energy demand (hyperexcitable brain) or decreased supply (mitochondrial impairment). However, it is uncertain how this precipitates an acute attack. Here, the central role of oxidative stress is adduced. Specifically, neurons’ antioxidant defenses rest ultimately on internally generated NADPH (reduced nicotinamide adenine dinucleotide phosphate), whose levels are tightly coupled to energy production. Mitochondrial NADPH is produced primarily by enzymes involved in energy generation, including isocitrate dehydrogenase of the Krebs (tricarboxylic acid) cycle; and an enzyme, nicotinamide nucleotide transhydrogenase (NNT), that depends on the Krebs cycle and oxidative phosphorylation to function, and that works in reverse, consuming antioxidants, when energy generation fails. In migraine aura, cortical spreading depression (CSD) causes an initial severe drop in level of NADH (reduced nicotinamide adenine dinucleotide), causing NNT to impair antioxidant defense. This is followed by functional hypoxia and a rebound in NADH, in which the electron transport chain overproduces oxidants. In migraine without aura, a similar biphasic fluctuation in NADH very likely generates oxidants in cortical regions farthest from capillaries and penetrating arterioles. Thus, the perturbations in brain energy demand and/or production seen in migraine are likely sufficient to cause oxidative stress, triggering an attack through oxidant-sensing nociceptive ion channels. Implications are discussed for the development of new classes of migraine preventives, for the current use of C57BL/6J mice (which lack NNT) in preclinical studies of migraine, for how a microembolism initiates CSD, and for how CSD can trigger a migraine.
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Abbreviations
- ADP:
-
Adenosine diphosphate
- AMP:
-
Adenosine monophosphate
- AMPK:
-
Adenosine monophosphate-activated protein kinase
- ASIC1:
-
Acid-sensing ion channel-1
- ATP:
-
Adenosine triphosphate
- CGRP:
-
Calcitonin gene-related peptide
- CNV:
-
Contingent negative variation
- CPEO:
-
Chronic progressive external ophthalmoplegia
- CSD:
-
Cortical spreading depression
- ETC:
-
Electron transport chain
- FADH2 :
-
Reduced flavin adenine dinucleotide
- FHM:
-
Familial hemiplegic migraine
- GLUT1:
-
Glucose transporter-1 (also called solute carrier 2A1, SLC2A1)
- IDH:
-
Isocitrate dehydrogenase enzyme
- mGlu5:
-
Metabotropic glutamate receptor type 5
- MELAS:
-
Mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes
- MERRF:
-
Myoclonic epilepsy and ragged red fibers syndrome
- MRS:
-
Magnetic resonance spectroscopy
- NADH:
-
Reduced nicotinamide adenine dinucleotide
- NADPH:
-
Reduced nicotinamide adenine dinucleotide phosphate
- NMDA:
-
N-methyl d-aspartate
- NNT:
-
Nicotinamide nucleotide transhydrogenase
- PMF:
-
Proton motive force
- PPP:
-
Pentose phosphate pathway
- Prx:
-
Peroxiredoxin
- ROS:
-
Reactive oxygen species
- SLC2A1:
-
Solute carrier 2A1 (also called glucose transporter 1; GLUT1)
- TRPA1:
-
Transient receptor potential ankyrin-1
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Acknowledgements
I am indebted to Thane Fremouw, PhD, Chair of the University of Maine Psychology Department, for suggesting this article and helping to provide the resources for writing it, to Peter W. Thompson, MD, of Northeast Pain Management in Bangor, Maine, for fascinating discussions related to this topic, and to the anonymous reviewers, who challenged and improved the article.
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Borkum, J.M. Brain Energy Deficit as a Source of Oxidative Stress in Migraine: A Molecular Basis for Migraine Susceptibility. Neurochem Res 46, 1913–1932 (2021). https://doi.org/10.1007/s11064-021-03335-9
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DOI: https://doi.org/10.1007/s11064-021-03335-9