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Brain Energy Deficit as a Source of Oxidative Stress in Migraine: A Molecular Basis for Migraine Susceptibility

“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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Correspondence to Jonathan M. Borkum.

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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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Keywords

  • Migraine
  • Oxidative stress
  • Mitochondria
  • Metabolic theory
  • Hypoxia
  • Nicotinamide nucleotide transhydrogenase