Skip to main content

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]


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.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2



Adenosine diphosphate


Adenosine monophosphate


Adenosine monophosphate-activated protein kinase


Acid-sensing ion channel-1


Adenosine triphosphate


Calcitonin gene-related peptide


Contingent negative variation


Chronic progressive external ophthalmoplegia


Cortical spreading depression


Electron transport chain


Reduced flavin adenine dinucleotide


Familial hemiplegic migraine


Glucose transporter-1 (also called solute carrier 2A1, SLC2A1)


Isocitrate dehydrogenase enzyme


Metabotropic glutamate receptor type 5


Mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes


Myoclonic epilepsy and ragged red fibers syndrome


Magnetic resonance spectroscopy


Reduced nicotinamide adenine dinucleotide


Reduced nicotinamide adenine dinucleotide phosphate


N-methyl d-aspartate


Nicotinamide nucleotide transhydrogenase


Proton motive force


Pentose phosphate pathway




Reactive oxygen species


Solute carrier 2A1 (also called glucose transporter 1; GLUT1)


Transient receptor potential ankyrin-1


  1. 1.

    Graham JR (1988) Migraine, Quo Vadis? Headache 28:681–688

    CAS  PubMed  Google Scholar 

  2. 2.

    Headache Classification Committee (2013) International classification of headache disorders, 3rd edition (beta version). Cephalalgia 33:629–808

    Google Scholar 

  3. 3.

    Borkum JM (2007) Chronic headaches: biology, psychology, and behavioral treatment. Lawrence Erlbaum Associates, Mahwah

    Google Scholar 

  4. 4.

    Buse DC, Loder EW, Gorman JA, Stewart WF, Reed ML, Fanning KM, Serrano D, Lipton RB (2013) Sex differences in the prevalence, symptoms, and associated features of migraine, probable migraine and other severe headache: results of the American Migraine Prevalence and Prevention (AMPP) study. Headache 53:1278–1299

    PubMed  Google Scholar 

  5. 5.

    GBD 2016, Disease and Injury Incidence and Prevalence Collaborators (2017) Global, regional, and national incidence, prevalence, and years lived with disability for 328 diseases and injuries for 195 countries, 1990–2016: a systematic analysis for the global burden of disease study 2016. Lancet 390:1211–1259

    Google Scholar 

  6. 6.

    Hu XH, Markson LE, Lipton RB, Stewart WF, Berger ML (1999) Burden of migraine in the United States: Disability and economic costs. Arch Intern Med 159:813–818

    CAS  PubMed  Google Scholar 

  7. 7.

    Gross EC, Lisicki M, Fischer D, Sándor PS, Schoenen J (2019) The metabolic face of migraine–from pathophysiology to treatment. Nat Rev Neurol 15:627–643.

    CAS  Article  PubMed  Google Scholar 

  8. 8.

    Borkum JM (2016) Migraine triggers and oxidative stress: a narrative review and synthesis. Headache 56:12–35

    PubMed  Google Scholar 

  9. 9.

    Fukai T, Ushio-Fukai M (2020) Cross-talk between NADPH oxidase and mitochondria: role in ROS signaling and angiogenesis. Cells 9:1849

    CAS  PubMed Central  Google Scholar 

  10. 10.

    Sies H (2017) Hydrogen peroxide as a central redox signaling molecule in physiological oxidative stress: oxidative eustress. Redox Biol 11:613–619

    CAS  PubMed  PubMed Central  Google Scholar 

  11. 11.

    Kozai D, Ogawa N, Mori Y (2014) Redox regulation of transient receptor potential channels. Antioxid Redox Signal 21:971–986

    CAS  PubMed  Google Scholar 

  12. 12.

    Marone IM, De Logu F, De Carvalho NR, Goncalves M, Benemei S, Ferreira J, Jain P, Puma SL, Bunnett NW, Geppetti P, Materazzi S (2018) TRPA1/NOX in the soma of trigeminal ganglion neurons mediates migraine-related pain of glyceryl trinitrate in mice. Brain 141:2312–2328

    PubMed  PubMed Central  Google Scholar 

  13. 13.

    Benemei S, Fusi C, Trevisan G, Geppetti P (2014) The TRPA1 channel in migraine mechanism and treatment. Br J Pharmacol 171:2552–2567

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Dussor G, Yan J, Xie JY, Ossipov MH, Dodick DW, Porreca F (2014) Targeting TRP channels for novel migraine therapeutics. ACS Chem Neurosci 5:1085–1096

    CAS  PubMed  Google Scholar 

  15. 15.

    Zhang X, Strassman AM, Novack V, Brin MF, Burstein R (2016) Extracranial injections of botulinum neurotoxin type A inhibit intracranial meningeal nociceptors’ responses to stimulation of TRPV1 and TRPA1 channels: are we getting closer to solving this puzzle? Cephalalgia 36:875–886

    CAS  PubMed  PubMed Central  Google Scholar 

  16. 16.

    Huang P, Kuo PH, Lee MT, Chiou LC, Fan PC (2018) Age-dependent anti-migraine effects of valproic acid and topiramate in rats. Front Pharmacol 9:1095

    CAS  PubMed  PubMed Central  Google Scholar 

  17. 17.

    Benemei S, De Logu F, Puma SL, Marone IM, Coppi E, Ugolini F, Liedtke W, Pollastro F, Appendino G, Geppetti P, Materazzi S, Nassini R (2017) The anti-migraine component of butterbur extracts, isopetasin, desensitizes peptidergic nociceptors by acting on TRPA1 cation channel. Br J Pharmacol 174:2897–2911

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Ghosh D, Levault KR, Brewer GJ (2014) Relative importance of redox buffers GSH and NAD(P)H in age-related neurodegeneration and Alzheimer disease-like mouse neurons. Aging Cell 13:631–640

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Yin F, Sancheti H, Patil I, Cadenas E (2016) Energy metabolism and inflammation in brain aging and Alzheimer’s disease. Free Radic Biol Med 100:108–122

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Zhang R, Al-Lamki R, Bai L, Streb JW, Miano JM, Bradley J, Min W (2004) Thioredoxin-2 inhibits mitochondria-located ASK1-mediated apoptosis in a JNK-independent manner. Circ Res 94:1483–1491

    CAS  PubMed  Google Scholar 

  21. 21.

    Islam MT (2017) Oxidative stress and mitochondrial dysfunction-linked neurodegenerative disorders. Neurol Res 39:73–82

    CAS  PubMed  Google Scholar 

  22. 22.

    Borkum JM (2018) The migraine attack as a homeostatic, neuroprotective response to brain oxidative stress: preliminary evidence for a theory. Headache 58:118–135

    PubMed  Google Scholar 

  23. 23.

    Borkum JM (2018) Harnessing migraines for neural regeneration. Neural Regen Res 13:609–615

    PubMed  PubMed Central  Google Scholar 

  24. 24.

    Amery WK (1982) Brain hypoxia: the turning-point in the genesis of the migraine attack? Cephalalgia 2:83–109

    CAS  PubMed  Google Scholar 

  25. 25.

    Amery WK (1985) Migraine and cerebral hypoxia: a hypothesis with pharmacotherapeutic implications. Cephalalgia 5(Suppl 2):131–133

    PubMed  Google Scholar 

  26. 26.

    Schoenen J (1994) Pathogenesis of migraine: the biobehavioural and hypoxia theories reconciled. Acta Neurol Belg 94:79–86

    CAS  PubMed  Google Scholar 

  27. 27.

    Reyngoudt H, Achten E, Paemeleire K (2012) Magnetic resonance spectroscopy in migraine: what have we learned so far? Cephalalgia 32:845–859

    PubMed  Google Scholar 

  28. 28.

    Younis S, Hougaard A, Vestergaard MB, Larsson HBW, Ashina M (2017) Migraine and magnetic resonance spectroscopy: a systematic review. Curr Opin Neurol 30:246–262

    PubMed  Google Scholar 

  29. 29.

    Reyngoudt H, Paemeleire K, Descamps B, De Deene Y, Achten E (2011) 31P-MRS demonstrates a reduction in high-energy phosphates in the occipital lobe of migraine without aura patients. Cephalalgia 31:1243–1253

    PubMed  Google Scholar 

  30. 30.

    Lodi R, Iotti S, Cortelli P, Pierangeli G, Cevoli S, Clementi V, Soriani S, Montagna P, Barbiroli B (2001) Deficient energy metabolism is associated with low free magnesium in the brains of patients with migraine and cluster headache. Brain Res Bull 54:437–441

    CAS  PubMed  Google Scholar 

  31. 31.

    Ødegård SS, Sand T, Engstrøm M, Stovner LJ, Zwart J-A, Hagen K (2011) The long-term effect of insomnia on primary headaches: a prospective population-based cohort study (HUNT-2 and HUNT-3). Headache 51:570–580

    PubMed  Google Scholar 

  32. 32.

    Karthik N, Sinha S, Taly AB, Kulkarni GB, Ramachandraiah CT, Rao S (2013) Alteration in polysomnographic profile in ‘migraine without aura’ compared to healthy controls. Sleep Med 14:211–214

    CAS  PubMed  Google Scholar 

  33. 33.

    Vgontzas A, Pavlović JM (2018) Sleep disorders and migraine: review of literature and potential pathophysiology mechanisms. Headache 58:1030–1039

    PubMed  PubMed Central  Google Scholar 

  34. 34.

    Smitherman TA, Walters AB, Davis RE, Ambrose CE, Roland M, Houle TT, Rains JC (2016) Randomized controlled pilot trial of behavioral insomnia treatment for chronic migraine with comorbid insomnia. Headache 56:276–291

    PubMed  Google Scholar 

  35. 35.

    Plante DT, Trksak GH, Jensen JE, Penetar DM, Ravichandran C, Riedner BA, Tartarini WL, Dorsey CM, Renshaw PF, Lukas SE, Harper DG (2014) Gray matter-specific changes in brain bioenergetics after acute sleep deprivation: a 31P magnetic resonance spectroscopy study at 4 Tesla. Sleep 37:1919–1927

    PubMed  PubMed Central  Google Scholar 

  36. 36.

    Montagna P, Pierangeli G, Cortelli P (2010) The primary headaches as a reflection of genetic darwinian adaptive behavioral responses. Headache 50:273–289

    PubMed  Google Scholar 

  37. 37.

    Lovati C, Giani L, D’Amico D, Mariani C (2017) Sleep, headaches and cerebral energy control: a synoptic view. Expert Rev Neurother 17:239–250

    CAS  PubMed  Google Scholar 

  38. 38.

    Coppola G, Pierelli F, Schoenen J (2007) Is the cerebral cortex hyperexcitable or hyperresponsive in migraine? Cephalalgia 27:1427–1439

    CAS  PubMed  Google Scholar 

  39. 39.

    Aurora SK, Wilkinson F (2007) The brain is hyperexcitable in migraine. Cephalalgia 27:1442–1453

    CAS  PubMed  Google Scholar 

  40. 40.

    Golla FL, Winter AL (1959) Analysis of cerebral responses to flicker in patients complaining of episodic headache. Electroencephalogr Clin Neurophysiol 11:539–549

    CAS  PubMed  Google Scholar 

  41. 41.

    de Tommaso M, Ambrosini A, Brighina F, Coppola G, Perrotta A, Pierelli F, Sandrini G, Valeriani M, Marinazzo D, Stramaglia S, Schoenen J (2014) Altered processing of sensory stimuli in patients with migraine. Nat Rev Neurol 10:144–155

    PubMed  Google Scholar 

  42. 42.

    Ambrosini A, Magis D, Schoenen J (2011) Migraine–clinical neurophysiology. Handb Clin Neurol 97:275–293

    Google Scholar 

  43. 43.

    Evers S, Quibeldey F, Grotemeyer K-H, Suhr B, Husstedt I-W (1999) Dynamic changes of cognitive habituation and serotonin metabolism during the migraine interval. Cephalalgia 19:485–491

    CAS  PubMed  Google Scholar 

  44. 44.

    Gantenbein AR, Sandor PS, Fritschy J, Turner R, Goadsby PJ, Kaube H (2013) Sensory information processing may be neuroenergetically more demanding in migraine patients. NeuroReport 24:202–205

    PubMed  Google Scholar 

  45. 45.

    Kokavec A (2016) Migraine: a disorder of metabolism? Med Hypotheses 97:117–130

    CAS  PubMed  Google Scholar 

  46. 46.

    Loder E (2002) What is the evolutionary advantage of migraine? Cephalalgia 22:624–632

    CAS  PubMed  Google Scholar 

  47. 47.

    Schoenen J (1996) Deficient habituation of evoked cortical potentials in migraine: a link between brain biology, behavior and trigeminovascular activation. Biomed Pharmacother 50:71–78

    CAS  PubMed  Google Scholar 

  48. 48.

    Hamel E (2007) Serotonin and migraine: biology and clinical implications. Cephalalgia 27:1293–1300

    CAS  PubMed  Google Scholar 

  49. 49.

    Cananzi AR, D’Andrea G, Perini F, Zamberlan F, Welch KM (1995) Platelet and plasma levels of glutamate and glutamine in migraine with and without aura. Cephalalgia 15:132–135

    CAS  PubMed  Google Scholar 

  50. 50.

    Ferrari A, Spaccapelo L, Pinetti D, Tacchi R, Bertolini A (2009) Effective prophylactic treatments of migraine lower plasma glutamate levels. Cephalalgia 29:423–429

    CAS  PubMed  Google Scholar 

  51. 51.

    Bathel A, Schweizer L, Stude P, Glaubitz B, Wulms N, Delicel S, Schmidt-Wilcke T (2018) Increased thalamic glutamate/glutamine levels in migraineurs. J Headache Pain 19:55.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  52. 52.

    Hoffmann J, Charles A (2018) Glutamate and its receptors as therapeutic targets for migraine. Neurotherapeutics 15:361–370

    CAS  PubMed  PubMed Central  Google Scholar 

  53. 53.

    Peek AL, Rebbeck T, Puts NAJ, Watson J, Aguila M-ER, Leaver AM (2020) Brain GABA and glutamate levels across pain conditions: a systematic literature review and meta-analysis of 1H-MRS studies using the MRS-Q quality assessment tool. Neuroimage 210:116532.

    CAS  Article  PubMed  Google Scholar 

  54. 54.

    Formicola D, Aloia A, Sampaolo S, Farina O, Diodato D, Griffiths LR, Gianfrancesco F, Di Iorio G, Esposito T (2010) Common variants in the regulative regions of GRIA1 and GRIA3 receptor genes are associated with migraine susceptibility. BMC Med Genet 11:103

    PubMed  PubMed Central  Google Scholar 

  55. 55.

    Anttila V, Stefansson H, Kallela M, Todt U, Terwindt GM, Calafato MS, Nyholt DR, Dimas AS, Freilinger T, Müller-Myhsok B et al (2010) Genome-wide association study of migraine implicates a common susceptibility variant on 8q22.1. Nat Genet 42:869–873

    CAS  PubMed  PubMed Central  Google Scholar 

  56. 56.

    Tottene A, Conti R, Fabbro A, Vecchia D, Shapovalova M, Santello M, van den Maagdenberg AMJM, Ferrari MD, Pietrobon D (2009) Enhanced excitatory transmission at cortical synapses as the basis for facilitated spreading depression in Ca(v)2.1 knockin migraine mice. Neuron 61:762–773

    CAS  PubMed  Google Scholar 

  57. 57.

    Vecchia D, Tottene A, van den Maagdenberg AMJM, Pietrobon D (2015) Abnormal cortical synaptic transmission in CaV2.1 knockin mice with the S218L missense mutation which causes a severe familial hemiplegic migraine syndrome in humans. Front Cell Neurosci 9:8.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  58. 58.

    Capuani C, Melone M, Tottene A, Bragina L, Crivellaro G, Santello M, Casari G, Conti F, Pietrobon D (2016) Defective glutamate and K+ clearance by cortical astrocytes in familial hemiplegic migraine type 2. EMBO Mol Med 8:967–986

    CAS  PubMed  PubMed Central  Google Scholar 

  59. 59.

    Storer RJ, Goadsby PJ (2013) Topiramate is likely to act outside of the trigeminocervical complex. Cephalalgia 33:291–300

    PubMed  Google Scholar 

  60. 60.

    Ferrari A, Rustichelli C, Baraldi C (2017) Glutamate receptor antagonists with the potential for migraine treatment. Expert Opin Investig Drugs 26:1321–1330

    CAS  PubMed  Google Scholar 

  61. 61.

    Dienel GA (2019) Brain glucose metabolism: integration of energetics with function. Physiol Rev 99:949–1045

    CAS  PubMed  Google Scholar 

  62. 62.

    Yu Y, Herman P, Rothman DL, Agarwal D, Hyder F (2018) Evaluating the gray and white matter energy budgets of human brain function. J Cereb Blood Flow Metab 38:1339–1353

    PubMed  Google Scholar 

  63. 63.

    Tiehuis LH, Koene S, Saris CGJ, Janssen MCH (2020) Mitochondrial migraine; a prevalence, impact and treatment efficacy cohort study. Mitochondrion 53:128–132

    CAS  PubMed  Google Scholar 

  64. 64.

    Kraya T, Deschauer M, Joshi PR, Zierz S, Gaul C (2018) Prevalence of headache in patients with mitochondrial disease: a cross-sectional study. Headache 58:45–52

    PubMed  Google Scholar 

  65. 65.

    Vollono C, Primiano G, Marca GD, Losurdo A, Servidei S (2018) Migraine in mitochondrial disorders: prevalence and characteristics. Cephalalgia 38:1093–1106

    PubMed  Google Scholar 

  66. 66.

    Montagna P, Sacquegna T, Martinelli P, Cortelli P, Bresolin N, Moggio M, Baldrati A, Riva R, Lugaresi E (1988) Mitochondrial abnormalities in migraine. Prelim Find Headache 28:477–480

    CAS  Google Scholar 

  67. 67.

    Sangiorgi S, Mochi M, Riva R, Cortelli P, Monari L, Pierangeli G, Montagna P (1994) Abnormal platelet mitochondrial function in patients affected by migraine with and without aura. Cephalalgia 14:21–23

    CAS  PubMed  Google Scholar 

  68. 68.

    Telford JE, Kilbride SM, Davey GP (2009) Complex I is rate-limiting for oxygen consumption in the nerve terminal. J Biol Chem 284:9109–9114

    CAS  PubMed  PubMed Central  Google Scholar 

  69. 69.

    Wilson DF, Rumsey WL, Green TJ, Vanderkooi JM (1988) The oxygen dependence of mitochondrial oxidative phosphorylation measured by a new optical method for measuring oxygen concentration. J Biol Chem 263:2712–2718

    CAS  PubMed  Google Scholar 

  70. 70.

    Almuqbil M, Rivkin MJ, Takeoka M, Yang E, Rodan LH (2018) Transient regional cerebral hypoperfusion during a paroxysmal hemiplegic event in GLUT1 deficiency syndrome. Eur J Paediatr Neurol 22:544–547

    PubMed  Google Scholar 

  71. 71.

    Mohammad S, Coman D, Calvert S (2014) Glucose transporter 1 deficiency syndrome and hemiplegic migraines as a dominant presenting clinical feature. J Paediatr Child Health 50:1025–1026

    PubMed  Google Scholar 

  72. 72.

    Prodan CI, Holland NR, Lenaerts ME, Parke JT (2002) Magnetic resonance angiogram evidence of vasopasm in familial hemiplegic migraine. J Child Neurol 17:470–472

    PubMed  Google Scholar 

  73. 73.

    Safier R, Cleves-Bayon C, Vaisleib I, Siddiqui A, Zuccoli G (2014) Magnetic resonance angiography evidence of vasospasm in children with suspected acute hemiplegic migraine. J Child Neurol 29:789–792

    PubMed  Google Scholar 

  74. 74.

    Lisicki M, D’Ostilio K, Coppola G, Scholtes F, Maertens de Noordhout A, Parisi V, Schoenen J, Magis D (2018) Evidence of an increased neuronal activation-to-resting glucose uptake ratio in the visual cortex of migraine patients: a study comparing 18FDG-PET and visual evoked potential. J Headache Pain 19:40.

    Article  Google Scholar 

  75. 75.

    Arngrim N, Schytz HW, Britze J, Amin FM, Vestergaard MB, Hougaard A, Wolfram F, de Koning PJH, Olsen KS, Secher NH, Larsson HBW, Olesen J, Ashina M (2016) Migraine induced by hypoxia: an MRI spectroscopy and angiography study. Brain 139:723–737

    PubMed  Google Scholar 

  76. 76.

    Schoenen J (2016) Hypoxia, a turning point in migraine pathogenesis? Brain 139:644–647

    PubMed  Google Scholar 

  77. 77.

    Blau JN, Cumings JN (1966) Method of precipitating and preventing migraine attacks. Br Med J 2:1242–1243

    CAS  PubMed  PubMed Central  Google Scholar 

  78. 78.

    Gray PA, Burtness HI (1935) Hypoglycemic headache. Endocrinology 19:549–560

    Google Scholar 

  79. 79.

    Roberts HJ (1967) Migraine and related vascular headaches due to diabetogenic hyperinsulinism. Observations on pathogenesis and rational treatment in 421 patients. Headache 7:41–62

    CAS  PubMed  Google Scholar 

  80. 80.

    Leão AAP (1944) Spreading depression of activity in cerebral cortex. J Neurophysiol 7:359–390

    Google Scholar 

  81. 81.

    Bolay H, Vuralli D, Goadsby PJ (2019) Aura and head pain: relationship and gaps in the translational models. J Headache Pain 20:94

    PubMed  PubMed Central  Google Scholar 

  82. 82.

    Stuart S, Griffiths LR (2012) A possible role for mitochondrial dysfunction in migraine. Mol Genet Genomics 287:837–844

    CAS  PubMed  Google Scholar 

  83. 83.

    Nicholls DG (2008) Oxidative stress and energy crises in neuronal dysfunction. Ann N Y Acad Sci 1147:53–60

    CAS  PubMed  Google Scholar 

  84. 84.

    Sparaco M, Feleppa M, Lipton RB, Rapoport AM, Bigal ME (2006) Mitochondrial dysfunction and migraine: evidence and hypotheses. Cephalalgia 26:361–372

    CAS  PubMed  Google Scholar 

  85. 85.

    Vanmolkot KR, Kors EE, Hottenga JJ, Terwindt GM, Haan J (2003) Novel mutations in the Na+, K+-ATPase pump gene ATP1A2 associated with familial hemiplegic migraine and benign familial infantile convulsions. Ann Neurol 54:360–366

    CAS  PubMed  Google Scholar 

  86. 86.

    Bailey DM (2019) Oxygen and brain death: back from the brink. Exp Physiol 104:1769–1779

    CAS  PubMed  Google Scholar 

  87. 87.

    Dreier JP, Major S, Foreman B, Winkler MKL, Kang E-J, Milakara D, Lemale CL, DiNapoli V, Hinzman JM, Woitzik J, Andaluz N, Carlson A, Hartings JA (2018) Terminal spreading depolarization and electrical silence in death of human cerebral cortex. Ann Neurol 83:295–310

    PubMed  PubMed Central  Google Scholar 

  88. 88.

    Toglia P, Ullah G (2019) Mitochondrial dysfunction and role in spreading depolarization and seizure. J Comput Neurosci 47:91–108

    PubMed  Google Scholar 

  89. 89.

    Kann O (2016) The interneuron energy hypothesis: implications for brain disease. Neurobiol Dis 90:75–85

    CAS  PubMed  Google Scholar 

  90. 90.

    Kiliç K, Karatas H, Dönmez-Demir B, Eren-Kocak E, Gursoy-Ozdemir Y, Can A, Petit J-M, Magistretti PJ, Dalkara T (2018) Inadequate brain glycogen or sleep increases spreading depression susceptibility. Ann Neurol 83:61–73

    PubMed  Google Scholar 

  91. 91.

    Yellen G (2018) Fueling thought: management of glycolysis and oxidative phosphorylation in neuronal metabolism. J Cell Biol 217:2235–2246

    CAS  PubMed  PubMed Central  Google Scholar 

  92. 92.

    Bolaños JP (2016) Bioenergetics and redox adaptations of astrocytes to neuronal activity. J Neurochem 139(Suppl. 2):115–125

    PubMed  PubMed Central  Google Scholar 

  93. 93.

    Berry BJ, Trewin AJ, Amitrano AM, Kim M, Wojtovich AP (2018) Use the protonmotive force: mitochondrial uncoupling and reactive oxygen species. J Mol Biol 430:3873–3891

    CAS  PubMed  PubMed Central  Google Scholar 

  94. 94.

    Bradshaw PC (2019) Cytoplasmic and mitochondrial NADPH-coupled redox systems in the regulation of aging. Nutrients 11(3):504.

    CAS  Article  PubMed Central  Google Scholar 

  95. 95.

    Takahashi T, Okuno M, Okamoto T, Kishi T (2008) NADPH-dependent coenzyme Q reductase is the main enzyme responsible for the reduction of non-mitochondrial CoQ in cells. BioFactors 32:59–70

    CAS  PubMed  Google Scholar 

  96. 96.

    Heck DE, Shakarjian M, Kim HD, Laskin JD, Vetrano AM (2010) Mechanisms of oxidant generation by catalase. Ann N Y Acad Sci 1203:120–125

    CAS  PubMed  PubMed Central  Google Scholar 

  97. 97.

    Kirkman HN, Gaetani GF (1984) Catalase: a tetrameric enzyme with four tightly bound molecules of NADPH. Proc Natl Acad Sci USA 81:4343–4347

    CAS  PubMed  PubMed Central  Google Scholar 

  98. 98.

    Morris G, Walder KR, Berk M, Marx W, Walker AJ, Maesl M, Puri BK (2020) The interplay between oxidative stress and bioenergetic failure in neuropsychiatric illnesses: can we explain it and can we treat it? Mol Biol Rep 47:5587–5620.

    CAS  Article  PubMed  Google Scholar 

  99. 99.

    Blacker TS, Duchen MR (2016) Investigating mitochondrial redox state using NADH and NADPH autofluorescence. Free Radic Biol Med 100:53–65

    CAS  PubMed  PubMed Central  Google Scholar 

  100. 100.

    Reitman ZJ, Yan H (2010) Isocitrate dehydrogenase 1 and 2 mutations in cancer: alterations at a crossroads of cellular metabolism. J Natl Cancer Inst 102:932–941

    CAS  PubMed  PubMed Central  Google Scholar 

  101. 101.

    Nickel AG, von Hardenberg A, Hohl M, Löffler JR, Kohlhaas M, Becker J, Reil J-C, Kazakov A, Bonnekoh J, Stadelmaier M et al (2015) Reversal of mitochondrial transhydrogenase causes oxidative stress in heart failure. Cell Metab 22:472–484

    CAS  PubMed  Google Scholar 

  102. 102.

    Fisher-Wellman KH, Lin C-T, Ryan TE, Reese LR, Gilliam LAA, Cathey BL, Lark DS, Smith CD, Muoio DM, Neufer PD (2015) Pyruvate dehydrogenase complex and nicotinamide nucleotide transhydrogenase constitute an energy-consuming redox circuit. Biochem J 467:271–280

    CAS  PubMed  Google Scholar 

  103. 103.

    Francisco A, Ronchi JA, Navarro CDC, Figueira TR, Castilho RF (2018) Nicotinamide nucleotide transhydrogenase is required for brain mitochondrial redox balance under hampered energy substrate metabolism and high-fat diet. J Neurochem 147:663–677

    CAS  PubMed  Google Scholar 

  104. 104.

    Rydström J (2006) Mitochondrial NADPH, transhydrogenase and disease. Biochim Biophy Acta 1757:721–726

    Google Scholar 

  105. 105.

    Chen R, Lai UH, Zhu L, Singh A, Ahmed M, Forsyth NR (2018) Reactive oxygen species formation in the brain at different oxygen levels: the role of hypoxia inducible factors. Front Cell Dev Biol 6:132

    PubMed  PubMed Central  Google Scholar 

  106. 106.

    Santos LRB, Muller C, de Souza AH, Takahashi HK, Spégel P, Sweet IR, Chae H, Mulder H, Jonas J-C (2017) NNT reverse mode of operation mediates glucose control of mitochondrial NADPH and glutathione redox state in mouse pancreatic β-cells. Mol Metab 6:535–547

    CAS  PubMed  PubMed Central  Google Scholar 

  107. 107.

    Wolf S, Hainz N, Beckmann A, Maack C, Menger MD, Tschernig T, Meier C (2016) Brain damage resulting from postnatal hypoxic-ischemic brain injury is reduced in C57BL/6J mice as compared to C57BL/6N mice. Brain Res 1650:224–231

    CAS  PubMed  Google Scholar 

  108. 108.

    Hoek JB, Rydström J (1988) Physiological roles of nicotinamide nucleotide transhydrogenase. Biochem J 254:1–10

    CAS  PubMed  PubMed Central  Google Scholar 

  109. 109.

    Ronchi JA, Francisco A, Passos LAC, Figueira TR, Castilho RF (2016) The contribution of nicotinamide nucleotide transhydrogenase to peroxide detoxification is dependent on the respiratory state and counterbalanced by other sources of NADPH in liver mitochondria. J Biol Chem 291:20173–20187

    CAS  PubMed  PubMed Central  Google Scholar 

  110. 110.

    Harriott AM, Takizawa T, Chung DY, Chen S-P (2019) Spreading depression as a preclinical model of migraine. J Headache Pain 20:45.

    Article  PubMed  PubMed Central  Google Scholar 

  111. 111.

    Takano T, Tian G-F, Peng W, Lou N, Lovatt D, Hansen AJ, Kasischke KA, Nedergaard M (2007) Cortical spreading depression causes and coincides with tissue hypoxia. Nat Neurosci 10:754–762

    CAS  PubMed  Google Scholar 

  112. 112.

    Berndt N, Kann O, Holzhütter H-G (2015) Physiology-based kinetic modeling of neuronal energy metabolism unravels the molecular basis of NAD(P)H fluorescence transients. J Cereb Blood Flow Metab 35:1494–1506

    CAS  PubMed  PubMed Central  Google Scholar 

  113. 113.

    Sheeran FL, Pepe S (2006) Energy deficiency in the failing heart: linking increased reactive oxygen species and disruption of oxidative phosphorylation rate. Biochim Biophys Acta 1757:543–552

    CAS  PubMed  Google Scholar 

  114. 114.

    Galeffi F, Somjen GG, Foster KA, Turner DA (2011) Simultaneous monitoring of tissue PO2 and NADH fluorescence during synaptic stimulation and spreading depression reveals a transient dissociation between oxygen utilization and mitochondrial redox state in rat hippocampal slices. J Cereb Blood Flow Metab 31:626–639

    CAS  PubMed  Google Scholar 

  115. 115.

    Kovács R, Kardos J, Heinemann U, Kann O (2005) Mitochondrial calcium ion and membrane potential transients follow the pattern of epileptiform discharges in hippocampal slice cultures. J Neurosci 25:4260–4269

    PubMed  PubMed Central  Google Scholar 

  116. 116.

    Kasischke KA, Lambert EM, Panepento B, Sun A, Gelbard HA, Burgess RW, Foster TH, Nedergaard M (2011) Two-photon NADH imaging exposes boundaries of oxygen diffusion in cortical vascular supply regions. J Cereb Blood Flow Metab 31:68–81

    CAS  PubMed  Google Scholar 

  117. 117.

    Yuzawa I, Sakadžić S, Srinivasan VJ, Shin HK, Eikermann-Haerter K, Boas DA, Ayata C (2012) Cortical spreading depression impairs oxygen delivery and metabolism in mice. J Cereb Blood Flow Metab 32:376–386

    CAS  PubMed  Google Scholar 

  118. 118.

    Zhao J, Levy D (2018) Dissociation between CSD-evoked metabolic perturbations and meningeal afferent activation and sensitization: implications for mechanisms of migraine headache onset. J Neurosci 38:5053–5066

    CAS  PubMed  PubMed Central  Google Scholar 

  119. 119.

    Takano T, Nedergaard M (2009) Deciphering migraine. J Clin Invest 119:16–19

    CAS  PubMed  Google Scholar 

  120. 120.

    Le Roux P, Menon DK, Citerio G, Vespa P, Bader MK, Brophy GM, Diringer MN, Stocchetti N, Videtta W, Armonda R et al (2014) Consensus summary statement of the international multidisciplinary consensus conference on multimodality monitoring in neurocritical care. Neurocrit Care 21:S1–S26

    PubMed  Google Scholar 

  121. 121.

    Hoffman WE, Charbel FT, Edelman G (1996) Brain tissue oxygen, carbon dioxide, and pH in neurosurgical patients at risk for ischemia. Anesth Analg 82:582–586

    CAS  PubMed  Google Scholar 

  122. 122.

    Schneider J, Berndt N, Papageorgiou IE, Maurer J, Bulik S, Both M, Draguhn A, Holzhütter H-G, Kann O (2019) Local oxygen homeostasis during various neuronal network activity states in the mouse hippocampus. J Cereb Blood Flow Metab 39:859–873

    PubMed  Google Scholar 

  123. 123.

    Abramov AY, Scorziello A, Duchen MR (2007) Three distinct mechanisms generate oxygen free radicals in neurons and contribute to cell death during anoxia and reoxygenation. J Neurosci 27:1129–1138

    CAS  PubMed  PubMed Central  Google Scholar 

  124. 124.

    Brand MD (2016) Mitochondrial generation of superoxide and hydrogen peroxide as the source of mitochondrial redox signaling. Free Radic Biol Medicine 100:14–31

    CAS  Google Scholar 

  125. 125.

    Mies G, Paschen W (1984) Regional changes of blood flow, glucose, and ATP content determined on brain sections during a single passage of spreading depression in rat brain cortex. Exp Neurol 84:249–258

    CAS  PubMed  Google Scholar 

  126. 126.

    Ayata C, Lauritzen M (2015) Spreading depression, spreading depolarizations, and the cerebral vasculature. Physiol Rev 95:953–993

    CAS  PubMed  PubMed Central  Google Scholar 

  127. 127.

    Hartings JA, Shuttleworth CW, Kirov SA, Ayata C, Hinzman JM, Foreman B, Andrew RD, Boutelle MG, Brennan KC, Carlson AP et al (2017) The continuum of spreading depolarizations in acute cortical lesion development: examining Leão’s legacy. J Cereb Blood Flow Metab 37:1571–1594

    PubMed  Google Scholar 

  128. 128.

    Zhou N, Gordon GRJ, Feighan D, MacVicar BA (2010) Transient swelling, acidification, and mitochondrial depolarization occurs in neurons but not astrocytes during spreading depression. Cereb Cortex 20:2614–2624

    PubMed  Google Scholar 

  129. 129.

    Gyulkhandanyan AV, Pennefather PS (2004) Shift in the localization of sites of hydrogen peroxide production in brain mitochondria by mitochondrial stress. J Neurochem 90:405–421

    CAS  PubMed  Google Scholar 

  130. 130.

    Viggiano A, Viggiano E, Valentino I, Monda M, Viggiano A, De Luca B (2011) Cortical spreading depression affects reactive oxygen species production. Brain Res 1368:11–18

    CAS  PubMed  Google Scholar 

  131. 131.

    Jiang L, Ma D, Grubb BD, Wang M (2019) ROS/TRPA1/CGRP signaling mediates cortical spreading depression. J Headache Pain 20:25.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  132. 132.

    Shatillo A, Koroleva K, Giniatullina R, Naumenko N, Slastnikova AA, Aliev RR, Bart G, Atalay M, Gu C, Khazipov R, Davletov B, Grohn O, Giniatullin R (2013) Cortical spreading depression induces oxidative stress in the trigeminal nociceptive system. Neuroscience 253:341–349

    CAS  PubMed  Google Scholar 

  133. 133.

    Charles AC, Baca SM (2013) Cortical spreading depression and migraine. Nat Rev Neurol 9:637–644

    PubMed  Google Scholar 

  134. 134.

    Hauge AW, Asghar MS, Schytz HW, Christensen K, Olesen J (2009) Effects of tonabersat on migraine with aura: a randomised, double-blind, placebo-controlled crossover study. Lancet Neurol 8:718–723

    CAS  PubMed  Google Scholar 

  135. 135.

    Vgontzas A, Burch R (2018) Episodic migraine with and without aura: key differences and implications for pathophysiology, management, and assessing risks. Curr Pain Headache Rep 22:78

    PubMed  Google Scholar 

  136. 136.

    Merikangas KR, Cui L, Richardson AK, Isler H, Khoromi S, Nakamura E, Lamers F, Rössler W, Ajdacic-Gross V, Gamma A, Angst J (2011) Magnitude, impact, and stability of primary headache subtypes: 30 year prospective Swiss cohort study. BMJ 343:d5076.

    Article  PubMed  PubMed Central  Google Scholar 

  137. 137.

    Skinhøj E, Olsen T (1990) Migraine with and without aura: the same disease due to cerebral vasospasm of different intensity. A hypothesis based on CBF studies during migraine. Headache 30:269–272

    Google Scholar 

  138. 138.

    Requardt RP, Wilhelm F, Rillich J, Winkler U, Hirrlinger J (2010) The biphasic NAD(P)H fluorescence response of astrocytes to dopamine reflects the metabolic actions of oxidative phosphorylation and glycolysis. J Neurochem 115:483–492

    CAS  PubMed  Google Scholar 

  139. 139.

    Hernansanz-Agustín P, Izquierdo-Álvarez A, Sánchez-Gómez FJ, Ramos E, Villa-Piña T, Lamas S, Bogdanova A, Martínez-Ruiz A (2014) Acute hypoxia produces a superoxide burst in cells. Free Radic Biol Med 71:146–156

    PubMed  Google Scholar 

  140. 140.

    Haan J, Terwindt GM, Ferrari MD (1997) Genetics of migraine. Neurol Clin 15:43–60

    CAS  PubMed  Google Scholar 

  141. 141.

    Bednarczyk EM, Remler B, Weikart C, Nelson AD, Reed RC (1998) Global cerebral blood flow, blood volume, and oxygen metabolism in patients with migraine headache. Neurology 50:1736–1740

    CAS  PubMed  Google Scholar 

  142. 142.

    Cao Y, Welch KMA, Aurora S, Vikinstad EM (1999) Functional MRI-BOLD of visually triggered headache in patients with migraine. Arch Neurol 56:548–554

    CAS  PubMed  Google Scholar 

  143. 143.

    Gelmers HJ (1982) Common migraine attacks preceded by focal hyperemia and parietal oligemia in the rCBF pattern. Cephalalgia 2:29–32

    CAS  PubMed  Google Scholar 

  144. 144.

    Woods RP, Jacoboni M, Mazziotta JC (1994) Brief report: bilateral spreading cerebral hypoperfusion during spontaneous migraine headache. N Engl J Med 331(25):1689–1692

    CAS  PubMed  Google Scholar 

  145. 145.

    Barkley GL, Tepley N, Nagel-Leiby S, Moran JE, Simkins RT, Welch KMA (1990) Magnetoencephalographic studies of migraine. Headache 30:428–434

    CAS  PubMed  Google Scholar 

  146. 146.

    Schoenen J, Jamart B, Delwaide PJ (1987) Cartographie electroencephalographique dans les migraines en periodes critique et intercritique. Rev Electroencephalogr Neurophysiol Clin 17:289–299

    CAS  PubMed  Google Scholar 

  147. 147.

    Gil-Gouveia R, Pinto J, Figueiredo P, Vilela PF, Martins IP (2017) An arterial spin labeling MRI perfusion study of migraine without aura attacks. Front Neurol 8:280.

    Article  PubMed  PubMed Central  Google Scholar 

  148. 148.

    Schiaffino S, Reggiani C, Kostrominova TY, Mann M, Murgia M (2015) Mitochondrial specialization revealed by single muscle fiber proteomics: focus on the Krebs cycle. Scand J Med Sci Sports 25(Suppl. 4):41–48

    PubMed  Google Scholar 

  149. 149.

    Lee J-H, Go Y, Kim D-Y, Lee SH, Kim O-H, Jeon YH, Kwon TK, Bae J-H, Song D-K, Rhyu IJ et al (2020) Isocitrate dehydrogenase 2 protects mice from high-fat diet-induced metabolic stress by limiting oxidative damage to the mitochondria from brown adipose tissue. Exp Mol Med 52:238–252

    CAS  PubMed  PubMed Central  Google Scholar 

  150. 150.

    Walsh K, Schena M, Flint AJ, Koshland DE Jr (1987) Compensatory regulation in metabolic pathways–responses to increases and decreases in citrate synthase levels. Biochem Soc Symp 54:183–195

    CAS  PubMed  Google Scholar 

  151. 151.

    Fukai T, Ushio-Fukai M (2020) Cross-talk between NADPH oxidase and mitochondria: role in ROS signaling and angiogenesis. Cells 9:1849.

    CAS  Article  PubMed Central  Google Scholar 

  152. 152.

    Brown JA, Sammy MJ, Ballinger SW (2020) An evolutionary, or “Mitocentric” perspective on cellular function and disease. Redox Biol 36:101568.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  153. 153.

    Tan JX, Finkel T (2020) Mitochondria as intracellular signaling platforms in health and disease. J Cell Biol 219:e202002179

    CAS  PubMed  PubMed Central  Google Scholar 

  154. 154.

    Malkov A, Ivanov AI, Popova I, Mukhtarov M, Gubkina O, Waseem T, Bregestovski P, Zilberter Y (2014) Reactive oxygen species initiate a metabolic collapse in hippocampal slices: potential trigger of cortical spreading depression. J Cereb Blood Flow Metab 34:1540–1549

    CAS  PubMed  PubMed Central  Google Scholar 

  155. 155.

    Dönmez-Demir B, Yemisci M, Kiliç K, Gürsoy-Özdemir Y, Söylemezoğlu F, Moskowitz M, Dalkara T (2018) Microembolism of single cortical arterioles can induce spreading depression and ischemic injury: a potential trigger for migraine and related MRI lesions. Brain Res 1679:84–90

    PubMed  Google Scholar 

  156. 156.

    Hoffmann U, Sukhotinsky I, Eikermann-Haerter K, Ayata C (2013) Glucose modulation of spreading depression susceptibility. J Cereb Blood Flow Metab 33:191–195

    CAS  PubMed  Google Scholar 

  157. 157.

    Goadsby PJ, Akerman S (2012) The trigeminovascular system does not require a peripheral sensory input to be activated–migraine is a central disorder. Cephalalgia 32:3–5

    PubMed  Google Scholar 

  158. 158.

    Vila-Pueyo M, Strother LC, Kefel M, Goadsby PJ, Holland PR (2019) Divergent influences of the locus coeruleus on migraine biology. Pain 160:385–394

    PubMed  Google Scholar 

  159. 159.

    Holland PR, Akerman S, Andreou AP, Karsan N, Wemmie JA, Goadsby PJ (2012) Acid-sensing ion channel 1: a novel therapeutic target for migraine with aura. Ann Neurol 72:559–563

    CAS  PubMed  Google Scholar 

  160. 160.

    Jalloh I, Carpenter KLH, Grice P, Howe DJ, Mason A, Gallagher CN, Helmy A, Murphy MP, Menon DK, Carpenter TA et al (2015) Glycolysis and the pentose phosphate pathway after human traumatic brain injury: microdialysis studies using 1,2–13C2 glucose. J Cereb Blood Flow Metab 35:111–120

    CAS  PubMed  Google Scholar 

  161. 161.

    Han HS, Kang G, Kim JS, Choi BH, Koo SH (2016) Regulation of glucose metabolism from a liver-centric perspective. Exp Mol Med 48:e218

    CAS  PubMed  PubMed Central  Google Scholar 

  162. 162.

    Rodriguez-Rodriguez P, Fernandez E, Almeida A, Bolanos JP (2012) Excitotoxic stimulus stabilizes PFKFB3 causing pentose-phosphate pathway to glycolysis switch and neurodegeneration. Cell Death Differ 19:1582–1589

    CAS  PubMed  PubMed Central  Google Scholar 

  163. 163.

    Vetrovoy O, Sarieva K, Lomert E, Nimiritsky P, Eschenko N, Galkina O, Lyanguzov A, Tyulkova E, Rybnikova E (2020) Pharmacological HIF1 inhibition eliminates downregulation of the pentose phosphate pathway and prevents neuronal apoptosis in rat hippocampus caused by severe hypoxia. J Mol Neurosci 70:635–646

    CAS  PubMed  Google Scholar 

  164. 164.

    Burmistrova O, Olias-Arjona A, Lapresa R, Jimenez-Blasco D, Eremeeva T, Shishov D, Romanov S, Zakurdaeva K, Almeida A, Fedichev PO, Bolaños JP (2019) Targeting PFKFB3 alleviates cerebral ischemia-reperfusion injury in mice. Sci Rep 9:11670

    PubMed  PubMed Central  Google Scholar 

  165. 165.

    Rodriguez-Rodriguez P, Almeida A, Bolaños JP (2013) Brain energy metabolism in glutamate-receptor activation and excitotoxicity: role for APC/C-Cdh1 in the balance glycolysis/pentose phosphate pathway. Neurochem Int 62:750–756

    CAS  PubMed  Google Scholar 

  166. 166.

    Herrero-Mendez A, Almeida A, Fernandez E, Maestre C, Moncada S, Bolanos JP (2009) The bioenergetic and antioxidant status of neurons is controlled by continuous degradation of a key glycolytic enzyme by APC/C-Cdh1. Nat Cell Biol 11:747–752

    CAS  PubMed  Google Scholar 

  167. 167.

    Baquer NZ, Hothersall JS, McLean P, Greenbaum AL (1977) Aspects of carbohydrate metabolism in developing brain. Dev Med Child Neurol 19:81–104

    CAS  PubMed  Google Scholar 

  168. 168.

    Jeon SM, Chanell NS, Hay N (2012) AMPK regulates NADPH homeostasis to promote tumour cell survival during energy stress. Nature 485:661–665

    CAS  PubMed  PubMed Central  Google Scholar 

  169. 169.

    Quaegebeur A, Segura I, Schmieder R, Verdegem D, Decimo I, Bifari F, Dresselaers T, Eelen G, Ghosh D, Davidson SM et al (2016) Deletion or inhibition of the oxygen sensor PHD1 protects against ischemic stroke via reprogramming of neuronal metabolism. Cell Metab 23:280–291

    CAS  PubMed  PubMed Central  Google Scholar 

  170. 170.

    Amorini AM, Lazzarino G, Di Pietro V, Signoretti S, Lazzarino G, Belli A, Tavazzi B (2016) Metabolic, enzymatic and gene involvement in cerebral glucose dysmetabolism after traumatic brain injury. Biochim Biophys Acta 1862:679–687

    CAS  PubMed  Google Scholar 

  171. 171.

    Pezzini A, Busto G, Zedde M, Gamba M, Zini A, Poli L, Caria F, De Giuli V, Simone AM, Pascarella R et al (2018) Vulnerability to infarction during cerebral ischemia in migraine sufferer. Stroke 49:573–578

    PubMed  Google Scholar 

  172. 172.

    Kletzien RF, Harris PKW, Foellmi LA (1994) Glucose-6-phosphate dehydrogenase: a “housekeeping” enzyme subject to tissue-specific regulation by hormones, nutrients, and oxidant stress. FASEB J 8:174–181

    CAS  PubMed  Google Scholar 

  173. 173.

    Luzzatto L, Arese P (2018) Favism and glucose-6-phosphate dehydrogenase deficiency. N Engl J Med 378:60–71

    CAS  PubMed  Google Scholar 

  174. 174.

    Gormley P, Anttila V, Winsvold BS, Palta P, Esko T, Pers TH, Farh K-H, Cuenca-Leon E, Muona M, Furlotte NA et al (2016) Meta-analysis of 375,000 individuals identifies 38 susceptibility loci for migraine. Nat Genet 48:856–865

    CAS  PubMed  PubMed Central  Google Scholar 

  175. 175.

    Xiao W, Loscalzo J (2020) Metabolic responses to reductive stress. Antioxid Redox Signal 32:1330–1347

    CAS  PubMed  PubMed Central  Google Scholar 

  176. 176.

    Paul BD, Sbodio JI, Snyder SH (2018) Cysteine metabolism in neuronal redox homeostasis. Trends Pharmacol Sci 39:513–524

    CAS  PubMed  PubMed Central  Google Scholar 

  177. 177.

    Sohal RS, Orr WC (2012) The redox stress hypothesis of aging. Free Radic Biol Med 52:539–555

    CAS  PubMed  Google Scholar 

  178. 178.

    Vesce S, Jekabsons MB, Johnson-Caldwell LI, Nicholls DG (2005) Acute glutathione depletion restricts mitochondrial ATP export in cerebellar granule neurons. J Biol Chem 280:38720–38728

    CAS  PubMed  Google Scholar 

  179. 179.

    Robinson RR, Dietz AK, Maroof AM, Asmis R, Forsthuber TG (2019) The role of glial-neuronal metabolic cooperation in modulating progression of multiple sclerosis and neuropathic pain. Immunotherapy 11:129–147

    CAS  PubMed  PubMed Central  Google Scholar 

  180. 180.

    Waldbaum S, Patel M (2010) Mitochondrial dysfunction and oxidative stress: a contributing link to acquired epilepsy? J Bioenerg Biomebr 42:449–455

    CAS  Google Scholar 

  181. 181.

    Emir UE, Raatz S, McPherson S, Hodges JS, Torkelson C, Tawfik P, White T, Terpstra M (2011) Noninvasive quantification of ascorbate and glutathione concentration in the elderly human brain. NMR Biomed 24:888–894

    CAS  PubMed  PubMed Central  Google Scholar 

  182. 182.

    Freitag FG (2013) Why do migraines often decrease as we age? Curr Pain Headache Rep 17:366

    PubMed  Google Scholar 

  183. 183.

    Barbanti P, Fabbrini G, Vanacore N, Rum A, Lenzi GL, Meco G, Cerbo R (2000) Dopamine and migraine: does Parkinson’s disease modify migraine course? Cephalalgia 20:720–723

    CAS  PubMed  Google Scholar 

  184. 184.

    Van Hilten JJ (1992) The migraine-dopamine link: do migraine and Parkinson’s disease coexist? Clin Neurol Neurosurg 94(Suppl):s168–s170

    PubMed  Google Scholar 

  185. 185.

    Heiker JT, Kern M, Kosacka J, Flehmig G, Stumvoll M, Shang E, Lohmann T, Dreßler M, Kovacs P, Blüher M, Klöting N (2013) Nicotinamide nucleotide transhydrogenase mRNA expression is related to human obesity. Obesity 21:529–534

    CAS  PubMed  Google Scholar 

  186. 186.

    Jansen NA, Dehghani A, Linssen MLM, Breukel C, Tolner EA, van den Maagdenberg AMJM (2020) First FHM3 mouse model shows spontaneous cortical spreading depolarizations. Ann Clin Transl Neurol 7:132–138

    CAS  PubMed  Google Scholar 

  187. 187.

    Tang C, Unekawa M, Shibata M, Tomita Y, Izawa Y, Sugimoto H, Ikeda K, Kawakami K, Suzuki N, Nakahara J (2020) Characteristics of cortical spreading depression and c-Fos expression in transgenic mice having a mutation associated with familial hemiplegic migraine 2. Cephalalgia.

    Article  PubMed  Google Scholar 

  188. 188.

    Yalcin N, Chen S-P, Yu ES, Liu T-T, Yen J-C, Atalay YB, Qin T, Celik F, van den Maagdenberg AMJM, Moskowitz MA, Ayata C, Eikermann-Haerter K (2019) Caffeine does not affect susceptibility to cortical spreading depolarization in mice. J Cereb Blood Flow Metab 39:740–750

    CAS  PubMed  Google Scholar 

  189. 189.

    Mulder IA, Li M, de Vries T, Qin T, Yanagisawa T, Sugimoto K, van den Bogaerdt A, Danser AHJ, Wermer MJH, van den Maagdenberg AMJM, MaassenVanDenBrink A, Ferrari MD, Ayata C (2020) Anti-migraine calcitonin gene-related peptide receptor antagonists worsen cerebral ischemic outcome in mice. Ann Neurol 88:771–784

    CAS  PubMed  PubMed Central  Google Scholar 

  190. 190.

    Pradhan AA, Smith ML, McGuire B, Tarash I, Evans CJ, Charles A (2014) Characterization of a novel model of chronic migraine. Pain 155:269–274

    CAS  PubMed  Google Scholar 

  191. 191.

    Toye AA, Lippiat JD, Proks P, Shimomura K, Bentley L, Hugill A, Mijat V, Goldsworthy M, Moir L, Haynes A, Quarterman J, Freeman HC, Ashcroft FM, Cox RD (2005) A genetic and physiological study of impaired glucose homeostasis control in C57BL/6J mice. Diabetologia 48:675–686

    CAS  PubMed  Google Scholar 

  192. 192.

    Arkblad EL, Egorov M, Shakhparonov M, Romanova L, Polzikov M, Rydstrom J (2002) Expression of proton-pumping nicotinamide nucleotide transhydrogenase in mouse, human brain and C. elegans. Comp Biochem Physiol B Biochem Mol Biol 133:13–21

    PubMed  Google Scholar 

  193. 193.

    Lopert P, Patel M (2014) Nicotinamide nucleotide transhydrogenase (Nnt) links the substrate requirement in brain mitochondria for hydrogen peroxide removal to the thioredoxin/peroxiredoxin (Trx/Prx) system. J Biol Chem 289:15611–15620

    CAS  PubMed  PubMed Central  Google Scholar 

  194. 194.

    Murphy MP, Hartley RC (2018) Mitochondria as a therapeutic target for common pathologies. Nat Rev Drug Discov 17:865–886

    CAS  PubMed  Google Scholar 

  195. 195.

    Bottani E, Lamperti C, Prigione A, Tiranti V, Persico N, Dario Brunetti D (2020) Therapeutic approaches to treat mitochondrial diseases: “one-size-fits-all” and “precision medicine” strategies. Pharmaceutics 12:1083.

    CAS  Article  PubMed Central  Google Scholar 

  196. 196.

    Barbiroli B, Iotti S, Lodi R (1999) Improved brain and muscle mitochondrial respiration with CoQ. An in vivo study by 31P-MR spectroscopy in patients with mitochondrial cytopathies. BioFactors 9:253–260

    CAS  PubMed  Google Scholar 

  197. 197.

    Markley HG (2012) CoEnzyme Q10 and riboflavin: the mitochondrial connection. Headache 52(Suppl 2):81–87

    PubMed  Google Scholar 

  198. 198.

    Parohan M, Sarraf P, Javanbakht MH, Ranji-Burachaloo S, Djalali M (2020) Effect of coenzyme Q10 supplementation on clinical features of migraine: a systematic review and dose-response meta-analysis of randomized controlled trials. Nutr Neurosci 23:868–875

    CAS  PubMed  Google Scholar 

  199. 199.

    Shrader WD, Amagata A, Barnes A, Hinman A, Jankowski O, Lee E, Kheifets V, Komatsuzaki R, Mollard P, Murase K, Rioux P, Wesson K, Miller G (2012) Towards a modern definition of vitamin E—evidence for a quinone hypothesis. Bioorg Med Chem Lett 22:391–395

    CAS  PubMed  Google Scholar 

  200. 200.

    Kalyanaraman B (2020) Teaching the basics of repurposing mitochondria-targeted drugs: from Parkinson’s disease to cancer and back to Parkinson’s disease. Redox Biol 36:101665.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  201. 201.

    Ismail H, Shakkour Z, Tabet M, Abdelhady S, Kobaisi A, Abedi R, Nasrallah L, Pintus G, Al-Dhaheri Y, Mondello S, El-Khoury R, Eid AH, Kobeissy F, Salameh J (2020) Traumatic brain injury: oxidative stress and novel anti-oxidants such as mitoquinone and edaravone. Antioxidants 9:943

    CAS  PubMed Central  Google Scholar 

  202. 202.

    Sagan KC, Cárcamo JM, Golde DW (2005) Vitamin C enters mitochondria via facilitative glucose transporter 1 (Glut1) and confers mitochondrial protection against oxidative injury. FASEB J 19:1657–1667

    Google Scholar 

  203. 203.

    Beyrath J, Pellegrini M, Renkema H, Houben L, Pecheritsyna S, van Zandvoort P, van den Broek P, Bekel A, Eftekhari P, Smeitink JAM (2018) KH176 safeguards mitochondrial diseased cells from redox stress-induced cell death by interacting with the thioredoxin system/peroxiredoxin enzyme machinery. Sci Rep 8:6577.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  204. 204.

    Brand MD, Goncalves RLS, Orr AL, Vargas L, Gerencser AA, Jensen MB, Wang YT, Melov S, Turk CN, Matzen JT, Dardov VJ, Petrassi HM, Meeusen SL, Perevoshchikova IV, Jasper H, Brookes PS, Ainscow EK (2016) Suppressors of superoxide-H2O2 production at site IQ of mitochondrial complex I protect against stem cell hyperplasia and ischemia-reperfusion injury. Cell Metab 24:582–592

    CAS  PubMed  PubMed Central  Google Scholar 

  205. 205.

    Orr AL, Vargas L, Turk CN, Baaten JE, Matzen JT, Dardov VJ, Attle SJ, Li J, Quackenbush DC, Goncalves RLS, Perevoshchikova IV, Petrassi HM, Meeusen SL, Ainscow EK, Brand MD (2015) Suppressors of superoxide production from mitochondrial complex III. Nat Chem Biol 11:834–836

    CAS  PubMed  PubMed Central  Google Scholar 

  206. 206.

    Atkinson M (1944) Migraine headache: some clinical observations on the vascular mechanism and its control. Ann Intern Med 21:990–997

    Google Scholar 

  207. 207.

    Prousky J, Seely D (2005) The treatment of migraines and tension-type headaches with intravenous and oral niacin (nicotinic acid): systematic review of the literature. Nutr J 4:3.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  208. 208.

    Velling DA, Dodick DW, Muir JJ (2003) Sustained release niacin for prevention of migraine headache. Mayo Clin Proc 78:770–771

    PubMed  Google Scholar 

  209. 209.

    Depeint F, Bruce WR, Mehta R, O’Brien PJ (2006) Mitochondrial function and toxicity: role of the B vitamin family on mitochondrial energy metabolism. Chem Biol Interact 163:94–112

    CAS  PubMed  Google Scholar 

  210. 210.

    Visser EJ, Drummond PD, Lee-Visser JLA (2020) Reduction in migraine and headache frequency and intensity with combined antioxidant prophylaxis (n-acetylcysteine, vitamin E, and vitamin C): a randomized sham-controlled pilot study. Pain Pract 20:737–747

    PubMed  Google Scholar 

  211. 211.

    Ghosh D, Levault KR, Brewer GJ (2014) Dual energy precursor and NRf2 activator treatment additively improve redox glutathione levels and neuron survival in aging and in Alzheimer mouse neurons upstream of ROS. Neurobiol Aging 35:179–190

    CAS  PubMed  Google Scholar 

  212. 212.

    Gross EC, Klement RJ, Schoenen J, D’Agostino DP, Fischer D (2019) Potential protective mechanisms of ketone bodies in migraine prevention. Nutrients 11:811

    CAS  PubMed Central  Google Scholar 

  213. 213.

    Maggioni F, Margoni M, Zanchin G (2011) Ketogenic diet in migraine treatment: a brief but ancient history. Cephalalgia 31:1150–1151

    PubMed  Google Scholar 

  214. 214.

    Di Lorenzo C, Coppola G, Bracaglia M, Di Lenola D, Evangelista M, Sirianni G, Rossi P, Di Lorenzo G, Serrao M, Parisi V et al (2016) Cortical functional correlates of responsiveness to short-lasting preventive intervention with ketogenic diet in migraine: a multimodal evoked potentials study. J Headache Pain 17:58

    PubMed  PubMed Central  Google Scholar 

  215. 215.

    Cherkas A, Holota S, Mdzinarashvili T, Gabbianelli R, Zarkovic N (2020) Glucose as a major antioxidant: when, what for, and why it fails? Antioxidants 9:140

    CAS  PubMed Central  Google Scholar 

  216. 216.

    Sato K, Kashiwaya Y, Keon CA, Tauchiya N, King MT, Radda GK, Chance B, Clarke K, Veech RL (1995) Insulin, ketone bodies, and mitochondrial energy transduction. FASEB J 9:651–658

    CAS  PubMed  Google Scholar 

  217. 217.

    Valdebenito R, Ruminot I, Garrido-Gerter P, Fernandez-Moncada I, Forero-Quintero L, Alegria K, Becker HM, Deitmer JW, Barros LF (2016) Targeting of astrocytic glucose metabolism by beta-hydroxybutyrate. J Cereb Blood Flow Metab 36:1813–1822

    CAS  PubMed  Google Scholar 

  218. 218.

    Alp R, Selek Ş, Alp Sİ, Taşkin A, Koçyiğit A (2010) Oxidative and antioxidative balance in patients of migraine. Eur Rev Med Pharmacol Sci 14:877–882

    CAS  PubMed  Google Scholar 

  219. 219.

    Neri M, Frustaci A, Milic M, Valdiglesias V, Fini M, Bonassi S, Barbanti P (2015) A meta-analysis of biomarkers related to oxidative stress and nitric oxide pathway in migraine. Cephalalgia 35:931–937

    PubMed  Google Scholar 

  220. 220.

    Lindquist BE, Shuttleworth CW (2014) Spreading depolarization-induced adenosine accumulation reflects metabolic status in vitro and in vivo. J Cereb Blood Flow Metab 34:1779–1790

    CAS  PubMed  PubMed Central  Google Scholar 

  221. 221.

    Guieu R, Devaux C, Henry H, Bechis G, Pouget J, Mallet D, Sampieri F, Juin M, Gola R, Rochat H (1998) Adenosine and migraine. Can J Neurol Sci 25:55–58

    CAS  PubMed  Google Scholar 

  222. 222.

    Fried NT, Elliott MB, Oshinsky ML (2017) The role of adenosine signaling in headache: a review. Brain Sci 7:30.

    CAS  Article  PubMed Central  Google Scholar 

  223. 223.

    Aytaç B, Coşkun Ö, Alioğlu B, Durak ZE, Büber S, Tapçi E, Öcal R, İnan LE, Durak İ, Yoldaş TK (2014) Decreased antioxidant status in migraine patients with brain white matter hyperintensities. Neurol Sci 35:1925–1929

    PubMed  Google Scholar 

  224. 224.

    Bolayir E, Celik K, Kugu N, Yilmaz A, Topaktas S, Bakir S (2004) Intraerythrocyte antioxidant enzyme activities in migraine and tension-type headaches. J Chin Med Assoc 67:263–267

    PubMed  Google Scholar 

  225. 225.

    Shimomura T, Kowa H, Nakano T, Kitano A, Marukawa H, Urakami K, Takahashi K (1994) Platelet superoxide dismutase in migraine and tension-type headache. Cephalalgia 14:215–218

    CAS  PubMed  Google Scholar 

  226. 226.

    Edvinsson L, Olesen IJ, Kingman TA, McCulloch J, Uddman R (1995) Modification of vasoconstrictor responses in cerebral blood vessels by lesioning of the trigeminal nerve: possible involvement of CGRP. Cephalalgia 15:373–383

    CAS  PubMed  Google Scholar 

  227. 227.

    González J, Valls N, Brito R, Rodrigo R (2014) Essential hypertension and oxidative stress: new insights. World J Cardiol 6:353–366

    PubMed  PubMed Central  Google Scholar 

  228. 228.

    Breslau N, Lipton RB, Stewart WF, Schultz LR, Welch KM (2003) Comorbidity of migraine and depression: investigating potential etiology and prognosis. Neurology 60:1308–1312

    CAS  PubMed  Google Scholar 

Download references


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.



Author information



Corresponding author

Correspondence to Jonathan M. Borkum.

Ethics declarations

Conflict of interest


Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

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).

Download citation


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