Wednesday, January 10, 2018

Molybdenum and Migraines, part 2

(continued from yesterday)

The Migraine Connection to Sulfite

The air pollutant sulfur dioxide, a sulfiting agent, appears linked to migraine occurrence.[1] [2] Chemically induced sulfite oxidase deficiency is toxic to the brain, primarily to the cerebral cortex and striatum,[3] which first area is connected to migraine susceptibility.[4] Sulfite is a catabolic product of hydrogen sulfide (H2S), an gasotransmitter found in the brain[5] that is connected to vasodilation,[6] and vasodilation has been repeatedly observed in connection with migraines. It is still unclear exactly how  H2S is broken down in the body; it was recently discovered that there appears to be a previously-unknown H2S catabolic pathway using neuroglobin.[7]

In most people, sulfite oxidase typically seems able to handle the amount of sulfite resulting from endogenous hydrogen sulfide production. However, in the absence of molybdenum, magnesium,[8] or P5P (active vitamin B6 is involved in making heme, which is part of sulfite oxidase),[9] sulfite oxidase might not reach necessary levels of activity, as those three nutrients are needed to form sulfite oxidase and its component, the molybdenum cofactor. Moreover, when sulfite oxidase is dealing with a high level of sulfite, nitrites also are substrates of the enzyme;[10] the connection between nitrites and migraines has much evidence behind it.[11] There is also evidence connecting sulfite consumption to migraines.[12]

mARC 1 and mARC 2

Two relatively recently discovered molybdenum-utilizing enzymes are the mARC 1 and mARC 2 enzymes. They appear to be involved with nitric oxide (NO) production,[13] and nitric oxide has long been reported to be involved with headaches, including migraines.[14] Molybdenum supplementation might, by facilitating optimal functioning of the mARC1 and mARC2 enzymes, contribute to appropriate NO production and possibly less migraine incidence. There is also evidence that interaction of NO and H2S is connected to migraine pathophysiology,[15] and NO and H2S cooperatively interact in many ways.[16]


I have written this because I have seen molybdenum help with migraines in several women with different etiologies (for example, one connected to hormonal fluctuation, one connected to neck injury and exacerbated by air pressure changes, and one of unknown causation), and I think current research supports a hypothesis that molybdenum does so by supporting optimal activity of the molybdenum-utilizing enzymes sulfite oxidase, mARC 1, and mARC 2. Because chronic migraines could be causing brain damage,[17] I think it urgent to explore whether molybdenum has potential to alleviate migraines.


[1] Szyszkowicz M, Rowe BH, Kaplan GG. Ambient sulphur dioxide exposure and emergency department visits for migraine in Vancouver, Canada. Int J Occup Med Environ Health 2009;22(1):7-12.
[2] Szyszkowicz M, Porada E. Ambient Sulphur Dioxide and Female ED Visits for Migraine. ISRN Neurology 2012;2012:279051.
[3] Grings M, Moura AP, Parmeggiani B, Motta MM, Boldrini RM, August PM, Matté C, Wyse AT, Wajner M, Leipnitz G. Higher susceptibility of cerebral cortex and striatum to sulfite neurotoxicity in sulfite oxidase-deficient rats. Biochim Biophys Acta 2016;1862(11):2063-2074.
[4] Lang E, Kaltenhäuser M, Neundörfer B, Seidler S. Hyperexcitability of the primary somatosensory cortex in migraine--a magnetoencephalographic study. Brain 2004;127(Pt 11):2459-2469.
[5] Gheibi S, Aboutaleb N, Khaksari M, Kalalian-Moghaddam H, Vakili A, Asadi Y, Mehrjerdi FZ, Gheibi A. Hydrogen sulfide protects the brain against ischemic reperfusion injury in a transient model of focal cerebral ischemia. J Mol Neurosci 2014;54(2):264-70.
[6] Bhatia, M. Hydrogen sulfide as a vasodilator. IUBMB Life 2005;57:603–606.
[7] Bilska-Wilkosz A, Iciek M, Górny M, Kowalczyk-Pachel D. The Role of Hemoproteins: Hemoglobin, Myoglobin and Neuroglobin in Endogenous Thiosulfate Production Processes. Int J Mol Sci 2017;18(6). pii: E1315. doi: 10.3390/ijms18061315.
[8] Mendel RR. The Molybdenum Cofactor. J Bio Chem 2013;288:13165-13172.
[9] Heinemann IU, Jahn M, Jahn D. Arch. The biochemistry of heme biosynthesis. Biochem Biophys 2008;474(2):238-251.
[10] Wang J, Krizowski S, Fischer-Schrader K, et al. Sulfite Oxidase Catalyzes Single-Electron Transfer at Molybdenum Domain to Reduce Nitrite to Nitric Oxide. Antioxidants & Redox Signaling 2015;23(4):283-294.
[11] D'Amico D, Ferraris A, Leone M, Catania A, Carlin A, Grazzi L, Bussone G. Increased plasma nitrites in migraine and cluster headache patients in interictal period: basal hyperactivity of L-arginine-NO pathway? Cephalalgia 2002 Feb;22(1):33-6.

[12] Millichap JG, Yee MM. The diet factor in pediatric and adolescent migraine. Ped Neurology 2003;28(1):9-15.

[13] Sparacino-Watkins CE, Tejero J, Sun B, Gauthier MC, Thomas J, Ragireddy V, Merchant BA, Wang J, Azarov I, Basu P, Gladwin MT. Nitrite reductase and nitric-oxide synthase activity of the mitochondrial molybdopterin enzymes mARC1 and mARC2. J Biol Chem 2014; 289(15):10345-10358.
[14] Thomsen LL, Olesen J. A pivotal role of nitric oxide in migraine pain. Ann N Y Acad Sci 1997;835:363-372.
[15] Wild V, Messlinger K, Fischer MJ. Hydrogen sulfide determines HNO-induced stimulation of trigeminal afferents. Neurosci Lett 2015; 602:104-109.
[16] Szabo C. Hydrogen sulfide, an enhancer of vascular nitric oxide signaling: mechanisms and implications. Am J Physiol Cell Physiol 2017 Jan 1;312(1):C3-C15.
[17] Asma Bashir, Richard B. Lipton, Sait Ashina, Messoud Ashina. Migraine and structural changes in the brain: A systematic review and meta-analysis. Neurology 2013;81(14):1260–1268.

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