1. Is your Ham a Hammerhead?
  2. How is Nitric Oxide made in the body?
  3. Nitrates reduce to nitrites; nitrites reduce to nitric oxide.
  4. Why do non-processed foods trigger fewer migraines?
  5. NO has many important bodily functions.
  6. Nitric oxide is a Gas and a Signaller.
  7. Nitric oxide is a Performance Enhancer.
  8. NO is also important for Erectile Function.
  9. Viagra is a Nitric Oxide pump that often causes Headache.
  10. Tongkat ali also is high in Nitric Oxide.
  11. NO is effective at inducing Headaches and Migraines.
  12. Stopping the enzymes that produced NO is effective in 60% of migraines.
  13. Nitric Oxide and CGRP are strongly linked in migraine.
  14. Nitric oxide increased CGRP Release Fourfold.
  15. Calcium also plays a big role in NO influenced migraine.
  16. Glutamate triggers an influx of Calcium and Sodium in the production of nitric oxide.
  17. Inflammation activates Astrocytes and/or Microglia which releases nitric oxide.
  18. Ginger inhibits the excessive production of nitric oxide.
  19. Nitric oxide is no laughing matter.
  20. Other facts about Nitric Oxide.
1.    Is your Ham a Hammerhead?

Bacon, hams, salami, pastrami, frankfurters and other sausages are common migraine triggers.

They give what are sometimes called “hotdog headaches. (1)

The main culprit in them seems to be the nitrates and nitrites used in making and preserving the modern versions of these processed and preserved meats.

Nitrates and nitrites convert into nitric oxide (NO).

Nitric oxide is crucial to the body, but too much nitric oxide can lead to migraines in those whose genetic constitution makes them sensitive. (2) (3) (4)

Here are some key points about nitric oxide in relation to migraines.

  • Glutamate is a major contributor to migraine
  • NO causes glutamate release from astrocytes and this might also lead to excitotoxicity and death of neurons (5)
  • NO raises calcium levels which increases glutamate release (6)
  • Glutamate increases NO
  • CGRP is a major peptide whose release is involved in migraine pain.
  • NO increases CGRP fourfold.

In addition many of these preserved meats contain MSG which also is a common trigger.

Nitrates and nitrites preserve the molecules in the meats and give them their red colouring. Preservatives are usually in the form of usually sodium nitrate and sodium nitrite. Also in these meats is haem (sometimes spelt heme).

2.    How is Nitric Oxide made in the body?

Nitric oxide is generated within the body from:

  1. the amino acid L-arginine and
  2. molecular oxygen in reactions catalyzed by complex nitric oxide synthases (NOS).
  3. Recently, an alternative pathway for nitric oxide generation was discovered, wherein nitrate (NO3-) and nitrite (NO2-) can be reduced back to nitric oxide.

This nitrate-nitrite-nitric oxide pathway is regulated differently to the classic L-arginine-nitric oxide synthase nitric oxide pathway, and it is greatly enhanced during hypoxia and acidosis.

[Acidosis is when your body fluids pH levels are imbalanced and have too much acid. Acid is produced in many bodily processes, and the body usually does a great job of maintaining pH stability. Common symptoms of acidosis include headaches, sleepiness, confusion, coma. Others are muscular seizures, weakness, shortness of breath, coughing, increased pulse rate, arrythmia, nausea and vomiting. – Ed]

Several lines of research now indicate that the nitrate-nitrite-nitric oxide pathway is involved in regulation of blood flow, cell metabolism, and signaling, as well as in tissue protection during hypoxia.

3. Nitrates reduce to nitrites; nitrites reduce to nitric oxide

Nitrates (NO3-) convert in the body to nitrites (NO2-).

Nitrites then convert to nitric oxide in the body.

It starts with your saliva. Anaerobic bacteria in the mouth reduce:

  • the nitrates (NO3-) to nitrites (NO2-), and
  • nitrites to nitric oxide (NO).

Scientists at the University of California San Diego found that migraine sufferers had higher levels of the genes responsible for reducing nitrates to nitrites to nitric acid through this salivary nitrate-nitrite-nitric oxide pathway. (7)

In other words people with more of these nitrate-nitrite-nitric oxide reducing genes convert more nitrate and nitrite into nitric oxide. They therefore seem to get more migraines.

[Be careful. When  scientists refer to a nitrate reducing gene they mean that it reduces from nitrate to nitrite. In this case NO3 loses an oxygen  atom and reduces to NO2.
Nitrite NO2 loses an oxygen atom to become nitric oxide – NO.
In each step it reduces by one oxygen atom. -Ed]

4. Why do non-processed foods trigger fewer migraines?

The correlation between nitrates-nitrites-nitric acid and migraines is well documented, but there is some lack of clarity as to why non-processed foods with high levels of nitrates are less quoted as migraine triggers.

A reason hypothesised is that veges like spinach, beets etc, while naturally high in nitrates, also contain antioxidants and minerals that moderate the downstream effects of NO, like moderating the release of glutamate.

There are some important things that you should know about nitric oxide and migraines.

5. NO has many important bodily functions

Nitric oxide is a brain booster.

It helps you learn, remember and retrieve things from memory.

It’s also a very important chemical that your body needs for numerous functions. It keeps the heart healthy, helps blood flow in the brain, heart, lungs, gut and in other parts of the body, and has many roles in the immune system too.

The body can produce its own NO through various mechanisms.

The body likes to keep NO at stable levels - homeostasis.

Too little can make you feel lethargic. Or be a contributor to memory loss, or loss of libido.

Too much nitric oxide, in the brain of a person who is sensitive, can lead to migraines. Hence, as earlier stated, the migraineur with more nitrate-nitrite-nitric oxide reducing genes ends up with more nitric oxide, and sometimes this is more than the body needs. This can lead to a migraine.

So if you are such a person and you eat a lot of processed meats, you could end up with migraine.

6. Nitric oxide is a Gas and a Signaller

One very important role that NO plays is in cellular signalling.  This is the process of cells talking to each other – and transmitting messages.

NO is a gas.

When it was discovered that NO, as a gas, was a neurotransmitter the scientific world was taken by surprise.

Being a gas and a cellular transmitter, it is known as a gasotransmitter. It has a very short life once it is released.

7. Nitric oxide is a Performance Enhancer

NO is well known amongst sporting folk for its ability to enhance physical prowess.

Muscle-builders try to increase their NO levels because it opens the veins wider (vasodilation). This allows more blood through the veins, bringing in more oxygen.

This causes the muscles to expand while enabling the body builder to get more weight and more repetitions per session as they pump iron. NO also reduces the recovery time needed post workout.

Competitive cyclists, who seem to grab a disproportionate number of headlines with their intricate knowledge of performance improvement, are also often big fans of increasing NO. This allows them to cycle faster, further and and for longer.

Many weightlifters’ supplements contain high levels of NO, and not surprisingly many who consume large quantities report an increased incidence of headaches. (8)

One popular natural NO booster is beetroot! Another popular way is by taking supplements like L-Arginine and L-Citrulline which you can buy from your local supplement suppliers.

(Having said that a team of Italian scientists said that their research suggests that “… a basal dysfunction in the L-arginine-NO pathway may be involved in the peripheral mechanisms predisposing subjects with neurovascular headaches to individual attacks.”) (4)

8. NO is also important for Erectile Function

On the topic of performance enhancement, NO is also a key driver in erectile function being responsible for the actions of the penile smooth muscle. (9)

9. Viagra is a Nitric Oxide pump that often causes Headache

The drug sildenafil citrate acts by filling the penis with nitric oxide that pumps blood into the erectile tissue. This drug is better known as Viagra.

However commonly reported side-effects of Viagra are headaches, cluster headaches and migraine according to neurologists at the National Defense Medical Center, Taipei, Taiwan. Their 2014 research paper claims that 25% of the patients that are prescribed Viagra experience headaches. (10)

In a Danish study at Copenhagen University, such is its power to induce migraine that the researchers used Viagra to cause migraines in a double-blind, randomized, placebo-controlled crossover study of 12 women to see if there was dilatation of the middle cerebral and temporal arteries during migraine. (11)

10. Tongkat ali also is high in Nitric Oxide

The South East Asian ‘natural viagra’ tongkat ali (eurycoma longifolia) also functions in the same way as Viagra and is naturally high in NO. (12)

While not well known outside South East Asia, if you ask many a man in Indonesia, Malaysia and the Philippines and he will most likely be able to hold forth with an opinion on the effects of tongkat ali.

11. NO is effective at inducing Headaches and Migraines

The 2003 study noted actions similar to those as seen after treatment with other migraine-inducing substances, such as histamine, CGRP and dipyridamole. (11)

The Danish scientists noted that NO was:

  1. At least as effective as nitroglycerin (glyceral trinitrate = GTN) in causing migraine and
  2. More effective than CGRP in causing a migraine and
  3. Probably also more effective than histamine at causing migraine.

They further noted however that NO may be involved in migraine induction by other mechanisms also, but that further separate studies for this were needed. (11)

In a 1994 study at the Department of Neurology, University of Copenhagen the researchers stated: Nitric oxide (NO) may play a key role in migraine … since glyceryl trinitrate [GTN nitroglycerine- ed] (a donor of NO) and histamine (which probably activates endothelial NO formation) both cause a pulsating dose-dependent headache with several migrainous characteristics. At relatively high doses of GTN, migraine sufferers develop stronger and more migraine-like headaches and more pronounced cerebral arterial dilatation than controls.

This corroborates the findings of a 1996 study by Lassen and others of the Un iversity of Copenhagen. (13)

Interestingly the researchers noted that after the infusion of nitroglycerine non-migraineurs remain headache-free while migraineurs develop a migraine-like attack. (3)

This is certainly consistent with the well accepted observation that in migraines “one man’s meat is another man’s poison.” This would also support the theory of a genetic link.

12. Stopping the enzymes that produced NO is effective in 60% of migraines

Treatment of spontaneous migraine attacks with an inhibitor of nitric oxide synthases, the enzymes that catalyse the production of NO, is effective in 60% of patients. (14)

13. Nitric Oxide and CGRP are strongly linked in migraine

Calcitonin gene-related peptide (CGRP) is identified as a key peptide in the mechanisms causing migraine.

Research identifies a strong link between CGRP and nitric oxide (NO) whose serum levels both increase during migraine attacks and other primary headaches.

As a result CGRP and NO are both considered key mediators in migraine, and clinical trials have shown that inhibiting NO synthase (NOS) and CGRP receptors is an effective way of treating migraine.

Most of these interactions are in the trigeminovascular system in migraine.

Both mediators facilitate nociceptive transmission, possibly via presynaptic mechanisms. (15) [Nociception is pain caused by damage to body tissue. -Ed]

[Pre-synaptic mechanisms refers to the things happening before reaching the synapse of the brain cells. This refers to mechanisms in things such as the microglia and astrocytes. The synapse is the gap between the two brain cells (neurons) which messages cross when one brain cell is sending a message to another. -Ed]

14. Nitric oxide increased CGRP Release Fourfold

A Missouri State University/University of Iowa 2006 study led by Dr Paul Durham also stated that calcitonin gene-related peptide (CGRP) and nitric oxide are involved in the underlying pathophysiology of migraine and other diseases involving neurogenic inflammation. (16) [Neurogenic means arising from, being caused or controlled by the nervous system or the nerves. - Ed]

Treatment of primary trigeminal ganglia cultures with nitric oxide donors caused a greater than four-fold increase in CGRP release compared with unstimulated cultures.

Similarly, CGRP promoter activity was also stimulated by nitric oxide donors and overexpression of inducible nitric oxide synthase (iNOS).  We saw above that reducing NO synthases was successful in treating 60% of migraines. (14)

A 2008 study led by the same Dr Durham who conducted the study above found that CGRP also stimulated NO synthesis and release from the trigeminal nerves (in nerves around the jaw where CGRP is released). (17)

So the takeaway is that: NO increases CGRP, and CGRP also stimulates NO. Each eggs the other on!

Thus, it seems likely that nitric oxide production and CGRP neuropeptide release are functionally linked in severe headaches. However, like so much of this puzzle the exact mechanisms by which NO controls CGRP gene expression in trigeminal neurons is not clear.

15. Calcium also plays a big role in NO influenced migraine

The Missouri State University team  found that while NO was involved with CGRP release the action required extracellular calcium. (16)

Nitric oxide was also greatly diminished when cells were stimulated in the absence of calcium.

Indiana University School of Medicine scientists’ 2007 data indicated that the “release of both glutamate and CGRP from trigeminal neurons is controlled by calcium channels and modulated by 5-HT signaling…. This is the first characterization of glutamate release from trigeminal neurons grown in culture.” (18)

We know that glutamate excites the neuron receptor with a positive charge. This causes the receptor to release the magnesium that blocks calcium from entering the neuron’s receptors. Too much glutamate leads to too much calcium in the neurons.

Excessive calcium influx leads to CGRP expression and NO expression. This can lead to neurotoxicity - migraine, seizure, epilepsy and other neurodegenerative disorders.

So magnesium and calcium work together in many parts of the body, and need to be in balance to avoid all manner of problems.

University of Virginia researchers have identified  this calcium as a switch.  They say that without calcium you won’t get inflammation. And what does the body use as its natural calcium blocker and mediator? Magnesium. (19) We talk about magnesium and migraine in more depth elsewhere on this website.

16. Glutamate triggers an influx of Calcium and Sodium in the production of nitric oxide.

A key driver in migraine is glutamate.

Glutamate is a building block of peptides and proteins. It is also important in the detoxification of ammonia. (20)

Excess glutamate accumulates in the synapse and over-excites NMDA receptors in the receving neuron. This triggers an influx of calcium and sodium, which stimulates the production of:

  1. reactive oxygen species (ROS) such as superoxide (O2-), and hydrogen peroxide (H2O2) as well as
  2. reactive nitrogen species (RNS) such as nitric oxide (NO) and peroxinitrite (ONOO).

High concentrations of intracellular calcium, ROS, and RNS induce cell death by:

1) damaging cellular architecture,

2) lipid peroxidation, which is where free radicals “steal” electrons from lipids in cell membranes damaging the membrane,

3) stimulating microglia to become toxic to the cells,

4) disrupting mitochondrial function, and

5) inducing pyknosis (chromatin condensation). (21)

Calcium entering the neurons (brain cells) via NMDA receptors may induce neuronal death (possibly via mitochondrial damage) and might further increase NO production by activation of neuronal nitric oxide synthase. (5)

As stated above glutamate triggers an influx of calcium. (21)

However a University of Indiana study shows “… that the release of both glutamate and CGRP from trigeminal neurons is controlled by calcium channels and modulated by 5-HT (serotonin) signaling”. (18)

17. Inflammation activates Astrocytes and/or Microglia which releases nitric oxide

When inflammation occurs in the brain this causes astrocytes and/or glia and microglia to become “activated”.

The activated glia and astrocytes mobilise to protect the brain cells.

They do this by destroying pathogens, removing the debris and then repairing the tissue.

Glial activation involves changes in cell structures and in gene expression, and the release of antigens, cell adhesion molecules, and cytokines.

Cytokines are proteins involved in cell signalling and have an effect on neighbouring cells. Some cytokines released are:

  • Tumor necrosis factor--a (TNF-a) and
  • Interleukin-1b (IL-1 b), and
  • The inducible isoform of nitric oxide synthase (iNOS).

Cambridge University scientists Anna Bal-Price and Guy Brown found that the release of NO from iNOS, which inhibits neuronal respiration resulting in glutamate release and subsequent excitotoxicity lead to the death of the neuron. (5) In layman’s tems the NO suffocates the neuron by starving it of oxygen. High levels of oxygen prevented the neuronal death by NO.

They found that NO causes glutamate release from astrocytes, and this might also contribute to excitotoxicity.

These are factors that are implicated in inducing migraine.

18. Ginger inhibits the excessive production of nitric oxide

Ginger works in many ways to suppress migraines.

This miracle plant has been used for thousands of years in this role, because …well … it worked and so it continued to be used all over the world.

Finally with the numerous advances in modern technology and the accessiblity of the internet science is now giving us many of the answers as to how ginger is so powerful in fighting migraines.

One of the ways ginger works is in the mediation of the effects of nitric oxide.

Ginger, orally ingested, seems to inhibit the activation of tumor necrosis factor-alpha (TNF-α), interleukin-1β (IL-1β), and inducible nitric oxide synthase (iNOS) and therefore NO. (22) (23)

In an Iranian study 100 arthritis patients supplementing with 1 gram of ginger powder daily were found to have “a significant decrease in serum concentration of CRP (C-Reactive Protein) and NO.” [One’s CRP  levels are used as a marker used to indicate levels of inflamation in the body. -Ed].

The Iranian study also reported four other studies with results consistent with their findings, each showing that ginger would suppress nitric oxide production. (23)

Researchers from Chang Gung University Taiwan found that 6-gingerol had an anti-inflammatory effect on mouse macrophages, the active constituent of ginger decreasing  iNOS and TNF-α expression. (24)

  1. A Korean research team Jung et al from Donguk University Korea showed that ginger hexane extract (GHE) significantly inhibited the excessive production of NO, protein, and mRNA expression of iNOS in mice. (25)
  2. An vitro study carried out by a research team from Japan “found that red ginger extract RGE (100 μg/mL) significantly inhibited NO production. [6]-shogaol, gingerdiols, and proanthocyanidins were identified as constituents that inhibited NO production.” (26)
  3. A 2013 Korean research team led by Han et al found that 12-dehydrogingerdione significantly suppressed the production of NO, this treatment suppressing the increase in iNOS levels. However, treatment of cells with LPS without 12-dehydrogingerdione significantly increased NO production. (27)
  4. In arthritis patients ginger was found to decrease the expression of TNF-α mRNA and protein, the production of COX2, and the NF-κB. [These are all involved in pain pathways. -Ed ]

    The study goes on to state “ … in addition, these crucial compounds suppress the synthesis of prostaglandin and leukotrienes by inhibiting the COX-2 and lipoxygenase pathways and also inflammation-involved pathways. This way, they can diminish the inflammation, which is a major contributor to many migraines.” (28)

A study at the College of Public Hygiene of Guangxi Medical University in China found that ginger’s 6-gingerol markedly reduced the production of nitric oxide (NO). It also noted the marked reduction in the levels of intracellular reactive oxygen species (ROS) and malondialdehyde (MDA), and increased superoxide dismutase (SOD) to indicate that 6-gingerol exhibited protective effects on brain cell death by reducing oxidative stress and inflammatory responses thereby exerting neuroprotective effects. (29)

19. Nitric oxide is no laughing matter

Take note that nitric oxide is easily mistaken for: 

  • Nitrous oxide (N2O), more commonly known as laughing gas, an anaesthetic, often used by doctors for example when patients are having intense pain during childbirth.
  • Nitrogen dioxide (NO2), a toxic gas formed when nitric oxide is oxidised. This is an air pollutant that is widespread.
20. Other facts about Nitric Oxide

The key lesson here is to be aware of the effects of eating processed meats.

In many cases they can lead to migraines in people who are sensitive.

Keeping a food diary will assist you to track whether a food, or a group of foods may cause a migraine. While in some people the effect is felt within hours, sometimes the effect can take up to 3 days, and can be exacerbated by mixing of various food groups.

References
  1. ”Hot-dog” headache: Individual susceptibility to nitrite. Henderson, W R and Raskin, N H. 1972, The Lancet, pp. 21162-1163.
  2. Increased nitric oxide stress is associated with migraine. Gruber, H J, et al. s.l. : Sage Journals, April 2010, Cephalagia, pp. 486-492. Author info: Clinical Institute of Medical and Chemical Laboratory Diagnostics, Graz, Austria.
  3. Nitric oxide is a key molecule in migraine and other vascular headaches. Olesen, J, Thomsen, L L and Iversen, H. 5, May 1994, Trends in Pharmacological Science, Vol. 15, pp. 149-153. Author info: Department of Neurology, University of Copenhagen, Glostrup Hospital, Denmark.
  4. Increased plasma nitrites in migraine and cluster headache patients in interictal period: basal hyperactivity of L-arginine-NO pathway? D'Amico, D, et al. 1, s.l. : Sage Journals, Feb 2002, Cephalagia, Vol. 22, pp. 33-36. Author info: Neurological Institute C. Besta, Milan, Italy.
  5. Inflammatory Neurodegeneration Mediated by Nitric Oxide from Activated Glia-Inhibiting Neuronal Respiration, Causing Glutamate Release and Excitotoxicity. Bal-Price, Anna and Brown, Guy C. 1 September 2001, The Journal of Neuroscience, Vol. 21 (17), pp. 6480-6491. Author info: Department of Biochemistry, University of Cambridge, Cambridge, CB2 1QW, United Kingdom.
  6. Nitric oxide induces rapid, calcium-dependent release of vesicular glutamate and ATP from cultured rat astrocytes. Bal-Price , A, Moneer, Z and Brown, G C. 3, s.l. : Wiley , Dec 2002, Glia, Vol. 40, pp. 312-323. Author info: Department of Biochemistry, University of Cambridge, Cambridge, UK.
  7. Migraines Are Correlated with Higher Levels of Nitrate-, Nitrite-, and Nitric Oxide-Reducing Oral Microbes in the American Gut Project Cohort. Gonzalez , Antonio, et al. 5, 18 October 2016, American Society for Microbiology, Vol. 1, pp. e00105-16. Creative Commons Attribution 4.0 International license. Author info: University of California San Diego, San Diego, California, USA.
  8. Orozco, Jeremy. The 3 Day Headache "Cure". Lexington : s.n., 2015. ISBN 151950134X.
  9. The role of nitric oxide in penile erection. Cartledge, Jon, Minhas, Suks and Eardley, Ian. 1, s.l. : Taylor & Francis Online, 2001, Expert Opinion on Pharmacotherapy, Vol. 2, pp. 95-107. Published online: 24 Feb 2005.
  10. Sildenafil can induce the onset of a cluster headache bout. Lin, Guan-Yu, et al. 5-6, 21 May 2014, Canadian Urological Association Journal, Vol. 8, pp. 378-380. Author info: Department of Neurology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, R.O.C..
  11. Migraine can be induced by sildenafil without changes in middle cerebral artery diameter. Kruuse, Christina, Thomsen, Lars Lykke and Birk, Steffen . 1, Copenhagen : Oxford Academic, 1 January 2003, Brain, Vol. 126, pp. 241-247. Author info: Department of Neurology, Glostrup Hospital, University of Copenhagen, Glostrup, Copenhagen, Denmark.
  12. Eurycoma longifolia: Medicinal Plant in the Prevention and Treatment of Male Osteoporosis due to Androgen Deficiency. Effendy, N M, et al. [ed.] Ima Nirwana Soelaiman. s.l. : Hindawi Publishing Corporation, 2012, Evidence-Based Complementary and Alternative Medicine. Department of Pharmacology, Faculty of Medicine, The National University of Malaysia, Kuala Lumpur, Malaysia.
  13. Histamine-1 receptor blockade does not prevent nitroglycerin induced migraine. Support for the NO-hypothesis of migraine. Lassen, L H, et al. 1996, European Journal of Clinical Pharmacology, Vol. 49 (5), pp. 335-339.
  14. Nitric oxide synthase inhibition in migraine. Lassen, L H, et al. 1997, Lancet, p. 349.
  15. CGRP and NO in the Trigeminal system: Mechanisms and role in Headache Generation. Messlinger, K, et al. 9, s.l. : American Headache Society, Oct 2012, Headache, Vol. 52, pp. 1411-1427. Author info: Institute of Physiology & Pathophysiology, University of Erlangen-Nürnberg, Erlangen, Germany.
  16. Nitric oxide regulation of calcitonin gene-related peptide gene expression in rat trigeminal ganglia neurons. Bellamy, J, et al. 8, April 2006, European Journal of Neuroscience, Vol. 23, pp. 2057–2066. Author info: Missouri State University & University of Iowa.
  17. Calcitonin gene-related peptide stimulation of nitric oxide synthesis and release from trigeminal ganglion glial cells. Durham, P L, Vause, C V and Li, J. 1196, s.l. : Elsevier, 27 February 2008 , Brain Research, pp. 22-32. Author info: Department of Biology, Missouri State University, Springfield, Missouri 65897, USA.
  18. Release of glutamate and CGRP from trigeminal ganglion neurons: Role of calcium channels and 5-HT1 receptor signaling. Yan, Xiao, Richter, Judith A and Hurley, Joyce. Indianapolis : BioMed Central, 16 April 2008, Molecular Pain, pp. 4-12. Author info: Indiana University School of Medicine, Indianapolis, USA 46202.
  19. Dean, Carolyn. The Magnesium Miracle. New York : Ballantine Books, Random House LLC, 2014. ISBN 978-0-345-49458-0.
  20. The stressed synapse: the impact of stress and glucocorticoids on glutamate transmission. Popoli, Maurizio, et al. 06 May 2013, Natural Review of Neuroscience, Vol. 13 (1), pp. 22-37. Author info: Popoli - University of Milano, Zhen Yan - University of New York, McEwen - Rockefeller University New York, Sanacora - Yale University School of Medicine.
  21. Systems, R&D. Neuronal Death by Glutamate Excitotoxicity: Protein Mediators & Strategies for Inhibition. R&D Systems. [Online] [Cited: 21 March 2018.] https://www.rndsystems.com/resources/articles/neuronal-death-glutamate-excitotoxicity-protein-mediators-strategies-inhibition.
  22. 1-Dehydro-[10]-gingerdione from ginger inhibits IKKβ activity for NF-κB activation and suppresses NF-κB-regulated expression of inflammatory genes. Lee, H Y, et al. 1, 2012, British Journal of Pharmacology, Vol. 167, pp. 128-140. Author info: College of Pharmacy, Chungbuk National University, Cheongju, Korea.
  23. Effect of ginger powder supplementation on nitric oxide and C-reactive protein in elderly knee osteoarthritis patients: A 12-week double-blind randomized placebo-controlled clinical trial. Naderi, Zahra, et al. 28 Jan 2015, Journal of Traditional Complementary Medicine, p. 6 (3). Author info: Yazd University of Medical Sciences, Yazd, Iran; Department of Pharmacology and Applied Medicine, Iranian Academic Center for Education Culture & Research (ACECR), Karaj; Shahid Sadoughi University of Medical Sciences, Yazd, Iran.
  24. 6-Gingerol inhibits ROS and iNOS through the suppression of PKC-alpha and NF-kappaB pathways in lipopolysaccharide-stimulated mouse macrophages. Lee , T Y, et al. 1, s.l. : Elsevier, 24 Apr 2009, Biochemical and Biophysical Research Communications, Vol. 382, pp. 134-139. Author info: Graduate Institute of Traditional Chinese Medicine, Chang Gung University, Kwei-Shan Tao-Yuan 333, Taiwan.
  25. Hexane fraction of Zingiberis Rhizoma Crudus extract inhibits the production of nitric oxide and proinflammatory cytokines in LPS-stimulated BV2 microglial cells via the NF-kappaB pathway. Jun, H W, et al. (6), s.l. : Elsevier, 04 Jun 2009, Food Chemical Toxicology, Vol. 47, pp. 1190-1197. Author info: Department of Herbology, College of Oriental Medicine, Dongguk University, Seok-Jang Dong, Gyeongju 780-714, Republic of Korea.
  26. Anti-inflammatory properties of red ginger (Zingiber officinale var. Rubra) extract and suppression of nitric oxide production by its constituents. Shimoda, H, et al. 1, s.l. : Mary Ann Liebert Inc Publishers, Feb 2010, Journal of Medicinal Food, Vol. 13. Author info: Research and Development Division, Oryza Oil & Fat Chemical Co., Ltd., Ichinomiya, Aichi, Japan.
  27. Anti-inflammatory effects of the Zingiber officinale roscoe constituent 12-dehydrogingerdione in lipopolysaccharide-stimulated Raw 264.7 cells. Han, Y A, et al. s.l. : Wiley Online Library, Aug 2013, Phytotherapy Research, pp. 1200-1205. Author info: Inhalation Toxicology Center, Jeonbuk Department of Non-human Primate, Korea Institute of Toxicology, Jeonbuk, Korea; College of Human Ecology, Seoul National University, Seoul, Korea.
  28. Osteoarthritis and nutrition. From nutraceuticals to functional foods: a systematic review of the scientific evidence. Ameye, Laurent G and Chee, Winnie SS. Lausanne : s.n., 19 July 2006, Arthritis Research & Therapy. Author info: Nutrition and Health Department, Nestlé Research Center, Vers-chez-les-Blanc, 1000 Lausanne 26, Switzerland.
  29. The Role of 6-Gingerol on Inhibiting Amyloid b Protein-Induced Apoptosis in PC12 Cells. Zeng, Gao-feng, et al. s.l. : Mary Ann Liebert, Inc, 2015, Rejuvenation Research, Vol. 18 (5). Author info: Guangxi Medical University, Guangxi, China.