Migraine attacks are based on inflammation and nitric oxide production in the capillaries and nervous tissues of the brain. Drugs that impact NO have a major impact on migraine attacks.
What do angina/nitroglycerine, impotency/Viagra, and migraine/L-NMMA have in common? The answer is nitric oxide, NO, a potent vasodilator and messenger molecule derived enzymatically from the basic amino acid arginine. NO is ubiquitous, short-lived and associated with inflammation. One of the NO synthetases (iNOS) that make NO is inducible as part of the suite of inflammation genes under the control of NFkB. Other NOS enzymes are controlled by cellular calcium levels and since we will be talking about neurons, it is important to mention that neurons ultimately release neurotransmitters when an action potential reaches the synapse and causes a sharp increase in calcium.
NO acts on a cell by activating cellular GMP cyclase to produce cyclic GMP. cGMP in turn can activate MAP kinase or NFkB. Viagra, by the way, enhances the vasodilation effects of NO by inhibiting the breakdown of cGMP and thereby causing more dilation with a limited amount of NO. Nitroglycerine/glyceryl trinitrate (GTN) increase the amount of NO available to endothelial cells and relax coronary arteries.
People who suffer from migraines, migraineurs, are sensitive to NO donors such as GTN and have a migraine attack after a delay of 4-6 hours. The headaches are not usually preceded by the typical visual auras. Non-migraineurs have no response. These results suggest the critical role of NO in the early stages of the migraine attack. Inhibition of NOS by L-NMMA reduces symptoms in most migraineurs after a spontaneous attack starts. Metabolites of NO also increase during migraine attacks.
Viagra, which blocks breakdown of cGMP, also induces migraine attacks in migraineurs and it does not cause dilation of the middle cerebral artery, suggesting that vasodilation may be only associated with migraine attacks, but not integral. Histamine can also cause attacks, but requires the NO pathway.
NO appears to act by increasing the release of the neuropeptide called CGRP, because NO initiated attacks can be stopped by drugs that block the CGRP receptor.
Inflammation is both a precondition for migraine attacks and a response to administration of NO donors such as GTN. The inflammatory transcription factor NFkB is activated by GTN and elevated levels of inflammatory cytokines, IL-1, IL-6, are released. Pretreatment with parthenolide, the active ingredient in feverfew, which is used as a migraine prophylaxis, reduced activation of NFkB by GTN. This observation reinforces the view that migraine pain results from NO induced inflammation.
The most effective and selective treatment for migraine headaches are drugs that block the action of the 5-hydroxytryptamine (5-HT) receptors, e.g. triptans, such as pizotifen and methysergide. The 5-HT receptor stimulation can result in NO production and blocking these receptors, blocks subsequent NO production, inflammation and pain. Prophylactic administration of NOS inhibitors, such as L-NMMA or NO scavengers, such as hydroxocobalamin, can reduce attacks.
There is substantial evidence that anti-inflammatory lifestyle and diets have a significant impact on the frequency and intensity of migraine attacks, because they minimize the participation of inflammation and its product, NO.
Neeb L, Reuter U. 2007. Nitric oxide in migraine. CNS Neurol Disord Drug Targets. 6(4):258-64.
Showing posts sorted by relevance for query migraine. Sort by date Show all posts
Showing posts sorted by relevance for query migraine. Sort by date Show all posts
Friday, October 3, 2008
Thursday, October 15, 2009
Migraine Headache Diet
Simple Guidelines to Lower Chronic Inflammation and Avoid Pain
If I stick to this Anti-Inflammatory Diet and Lifestyle, I don’t get migraine headaches any more. I can still get a migraine, if I let myself get very dehydrated or drift into carbohydrate excess, but I am shocked when it happens. I can still enjoy chocolate and coffee. Avoiding the headaches is under my control and the diet is healthy and easy to follow.
Chronic Inflammation Is the Foundation for Migraine Headaches
The details and rationale for the Basic Anti-inflammatory Diet and Lifestyle are discussed in many articles on this blog. The guiding logic is that migraine headaches are based on chronic inflammation, although in each individual case there may be specific health problems that contribute and trigger migraines. If the chronic inflammation is removed, then migraines can’t happen or are reduced in frequency and/or severity.
Common Migraine Guidelines Point to Inflammation as the Problem
Feverfew is present on all of the lists of traditional treatments to avoid migraines. Extracts of feverfew contain parthenolide, a sesquiterpene lactone, that has been shown in mouse studies to inhibit activation of NFkB, the inflammation transcription factor. Stress reduction, acupuncture, etc. all point to vagal stimulation to reduce chronic inflammation. I would also recommend that migraine sufferers investigate vagal stimulation exercises to augment the basic diet and exercise to eliminate chronic inflammation.
Anti-inflammatory Diet in a Nutshell
Typical Meals for a Healthy Head
Why Conventional Diet Wisdom Gives You a Headache
The government food pyramid was designed by the food industry and was never supported by evidence from the biomedical literature. Research shows that saturated fats actually lower heart disease. Polyunsaturated fats in common vegetable oils are a major source of chronic diet-based inflammation. Starch/sugar raises triglycerides, not dietary fats. Grains are a major source of inflammation, because of the high incidence of gluten intolerance, the high content of hyperglycemic starch (even in whole grain breads, etc.) and in the support of gut biofilms based on Klebsiella, a contributor to Crohn’s and other autoimmune diseases. Blood lipid levels were not associated with heart disease and lowering these levels with statins does not improve health. Lowering inflammation uniformly improves health, as well as eliminating migraines.
If I stick to this Anti-Inflammatory Diet and Lifestyle, I don’t get migraine headaches any more. I can still get a migraine, if I let myself get very dehydrated or drift into carbohydrate excess, but I am shocked when it happens. I can still enjoy chocolate and coffee. Avoiding the headaches is under my control and the diet is healthy and easy to follow.
Chronic Inflammation Is the Foundation for Migraine Headaches
The details and rationale for the Basic Anti-inflammatory Diet and Lifestyle are discussed in many articles on this blog. The guiding logic is that migraine headaches are based on chronic inflammation, although in each individual case there may be specific health problems that contribute and trigger migraines. If the chronic inflammation is removed, then migraines can’t happen or are reduced in frequency and/or severity.
Common Migraine Guidelines Point to Inflammation as the Problem
Feverfew is present on all of the lists of traditional treatments to avoid migraines. Extracts of feverfew contain parthenolide, a sesquiterpene lactone, that has been shown in mouse studies to inhibit activation of NFkB, the inflammation transcription factor. Stress reduction, acupuncture, etc. all point to vagal stimulation to reduce chronic inflammation. I would also recommend that migraine sufferers investigate vagal stimulation exercises to augment the basic diet and exercise to eliminate chronic inflammation.
Anti-inflammatory Diet in a Nutshell
- Vitamin D -- deficiency is common... even with adequate sun exposure
- Low carbs -- starch is hyperglycemic, grain gluten intolerance is very common
- Vegetable oils -- only olive oil is safe (trans fats are dangerous), butter is better
- Fish oil -- omega-3 oils can reduce chronic inflammation
- High fructose corn syrup -- eliminate all sources
- Saturated Fats -- safer than polyunsaturated fats, major source of calories
Typical Meals for a Healthy Head
Breakfast -- eggs, bacon, sausage, stewed tomatoes, cottage cheese, coffee, yogurt (low sugar, no HFCS) (avoid cereal, pancakes, waffles, toast, etc.)
- Lunch -- soup, salad, chicken, ham, tuna, vegetables, modest amounts of fruit, etc. (avoid bread, buns, potatoes, pasta, rice), keep the carbs to less than 50 grams
- Dinner -- fish, meat, vegetables, 50 grams of carbs (avoid grains)
Why Conventional Diet Wisdom Gives You a Headache
The government food pyramid was designed by the food industry and was never supported by evidence from the biomedical literature. Research shows that saturated fats actually lower heart disease. Polyunsaturated fats in common vegetable oils are a major source of chronic diet-based inflammation. Starch/sugar raises triglycerides, not dietary fats. Grains are a major source of inflammation, because of the high incidence of gluten intolerance, the high content of hyperglycemic starch (even in whole grain breads, etc.) and in the support of gut biofilms based on Klebsiella, a contributor to Crohn’s and other autoimmune diseases. Blood lipid levels were not associated with heart disease and lowering these levels with statins does not improve health. Lowering inflammation uniformly improves health, as well as eliminating migraines.
Saturday, October 4, 2008
Migraine, Heparin, Glucosamine
Is it possible to repair the damage that leads to migraine headaches? If chronic inflammation is a risk factor, then depletion of brain heparan sulfate proteoglycans could be repaired temporarily with heparin or gradually with glucosamine.
Mast cells, the secreters of histamine in allergic reactions, also secrete heparin at the same time. In fact, cattle and swine intestines are the sources of commercial heparin. The crude source of heparin became dangerously apparent in recent scandals over the adulteration of Chinese heparin raw materials with hypersulfated chondroitin sulfate. But why is heparin secreted along with histamine in mast cells and what does this have to do with migraine headaches and glucosamine?
A basic observation is that migraineurs who receive heparin or glucosamine treatments for other symptoms, see relief from their headaches. Heparin treatments can produce dramatic effects that may be shortlived. Glucosamine may require substantial amounts taken orally for four to six weeks before migraines abate. Heparin and glucosamine are both effective, but how do they work?
Heparin and glucosamine therapies are both awkward. Heparin is rapidly internalized and degraded by cells. Glucosamine is also rapidly taken up and processed. In both cases, ingested heparin or glucosamine do not enter the blood stream. I think it is highly unlikely that either taken orally will have their effects directly in the brain or joints, simply because they are commonly metabolized molecules. Glucosamine may be a building block for heparin and other glycosaminoglycans, but it just passes directly into glucose metabolism, so that logical connection is unimportant in joint pain or migraines. I covered glucosamine in more detail as an anti-inflammatory molecule in another article, so here I will only emphasize that glucosamine is very effective for prophylaxis of migraine headaches.
Heparin can have an impact orally for some bowel diseases, but for headaches it must be administered IV or by inhaling. The major point here is that heparan sulfate proteoglycans (proteins with long heparan polysaccharides) mediate most of the hormonal signaling by mediating the binding of hormones to their receptors. Heparan fragments, called heparin, are a mixture of molecules that may interfere with or augment signaling, dependent on the quality of the heparinoids and the signal pathways under consideration. In most cases, there are so many different hormones and receptors involved, that it is more straightforward to try heparin to see if it works, rather than attempt to sort out all of the side reactions. If heparin does work, it should also be noticed that the amount of heparin required for an anticoagulant effect is on the high side, reflecting the depletion of circulating heparin.
Mast cells and histamine release have been implicated in migraine, but we have to return to the question of why heparin is normally released at the same time. From my own experiments with chondrocytes, the cartilage secreting, developmentally related sisters of the arterial endothelial cells, I would expect that inflammation inhibits heparin synthesis. Prevailing inflammation may reduce the production of heparin by mast cells and neuronal cells. As a result, triggering mast cells may release histamine into heparin-depleted brain tissue. If heparin normally serves to control the spread of the inflammatory signal from mast cells, then the absence of adequate heparin may lead to a spreading inflammation, a kind of neurological shock and awe. Addition of circulating heparin may temporarily repair the blood brain barrier, just as it does the lining of the bladder with interstitial cystitis or the kidneys in diabetes or the intestines in protein lossing enteropathy.
It appears that migraines are based on chronic inflammation of the brain and an associated compromise of the blood brain barrier. The source of the chronic inflammation may be shared with other degenerative and autoimmune diseases that lead to migraine attacks. Underlying infections may be hard to identify. The solution is to reestablish the blood brain barrier by eliminating chronic inflammation. Separate reports indicate that glucosamine, omega-3 fatty acids and anti-oxidants are all effective in reducing migraines. It seems obvious that the first step would be to begin an anti-inflammatory lifestyle (including exercise, dental hygiene, etc.) supported by an appropriate diet.
Mast cells, the secreters of histamine in allergic reactions, also secrete heparin at the same time. In fact, cattle and swine intestines are the sources of commercial heparin. The crude source of heparin became dangerously apparent in recent scandals over the adulteration of Chinese heparin raw materials with hypersulfated chondroitin sulfate. But why is heparin secreted along with histamine in mast cells and what does this have to do with migraine headaches and glucosamine?
A basic observation is that migraineurs who receive heparin or glucosamine treatments for other symptoms, see relief from their headaches. Heparin treatments can produce dramatic effects that may be shortlived. Glucosamine may require substantial amounts taken orally for four to six weeks before migraines abate. Heparin and glucosamine are both effective, but how do they work?
Heparin and glucosamine therapies are both awkward. Heparin is rapidly internalized and degraded by cells. Glucosamine is also rapidly taken up and processed. In both cases, ingested heparin or glucosamine do not enter the blood stream. I think it is highly unlikely that either taken orally will have their effects directly in the brain or joints, simply because they are commonly metabolized molecules. Glucosamine may be a building block for heparin and other glycosaminoglycans, but it just passes directly into glucose metabolism, so that logical connection is unimportant in joint pain or migraines. I covered glucosamine in more detail as an anti-inflammatory molecule in another article, so here I will only emphasize that glucosamine is very effective for prophylaxis of migraine headaches.
Heparin can have an impact orally for some bowel diseases, but for headaches it must be administered IV or by inhaling. The major point here is that heparan sulfate proteoglycans (proteins with long heparan polysaccharides) mediate most of the hormonal signaling by mediating the binding of hormones to their receptors. Heparan fragments, called heparin, are a mixture of molecules that may interfere with or augment signaling, dependent on the quality of the heparinoids and the signal pathways under consideration. In most cases, there are so many different hormones and receptors involved, that it is more straightforward to try heparin to see if it works, rather than attempt to sort out all of the side reactions. If heparin does work, it should also be noticed that the amount of heparin required for an anticoagulant effect is on the high side, reflecting the depletion of circulating heparin.Mast cells and histamine release have been implicated in migraine, but we have to return to the question of why heparin is normally released at the same time. From my own experiments with chondrocytes, the cartilage secreting, developmentally related sisters of the arterial endothelial cells, I would expect that inflammation inhibits heparin synthesis. Prevailing inflammation may reduce the production of heparin by mast cells and neuronal cells. As a result, triggering mast cells may release histamine into heparin-depleted brain tissue. If heparin normally serves to control the spread of the inflammatory signal from mast cells, then the absence of adequate heparin may lead to a spreading inflammation, a kind of neurological shock and awe. Addition of circulating heparin may temporarily repair the blood brain barrier, just as it does the lining of the bladder with interstitial cystitis or the kidneys in diabetes or the intestines in protein lossing enteropathy.
It appears that migraines are based on chronic inflammation of the brain and an associated compromise of the blood brain barrier. The source of the chronic inflammation may be shared with other degenerative and autoimmune diseases that lead to migraine attacks. Underlying infections may be hard to identify. The solution is to reestablish the blood brain barrier by eliminating chronic inflammation. Separate reports indicate that glucosamine, omega-3 fatty acids and anti-oxidants are all effective in reducing migraines. It seems obvious that the first step would be to begin an anti-inflammatory lifestyle (including exercise, dental hygiene, etc.) supported by an appropriate diet.
Friday, October 3, 2008
Toulouse-Lautrec
Cathepsin K and Heparin
The power of simple sequence pattern analysis in predicting protein behavior is illustrated in the case of Cathepsin K, a papain-like cysteine protease, involved in many degenerative diseases, bone development and Pycnodysostosis (Toulouse-Lautrec syndrome.) Triplets of basic amino acids are typical of heparin binding proteins that are internalized.
I admit that I am obsessed with inflammation and heparin. My daughters automatically yell out “Give him heparin!” when a patient on ER has a severe migraine attack. They think it is a good joke until the savvy doc reveals the latest approach and actually injects heparin with satisfying results. Heparin and inflammation are intimately involved and I predict that blood tests that determine the quality and quantity of protein-bound heparin, will ultimately be used as measures of chronic inflammation, as well as revealing a variety of diseases.
I have a habit of examining the molecular basis of diseases that I encounter on TV, in newspapers or in books. Wikipedia is my first source, followed by the National Center for Biotechnology Information (NCBI). As soon as I find the genes/proteins involved, I check to see if the structures has been determined by X-ray crystallography or NMR, and then I look at the amino acid sequence. I check for pairs or triplets of basic amino acids. Invariably the pairs are matched with a neighboring basic amino acid, and that is a putative heparin-binding domain. Triplets almost always indicate secreted proteins that are brought back into cells dependent on strong affinity for recycled heparan sulfate proteoglycans. Within minutes of hearing about a new disease, I usually know something about the molecules involved and particularly whether or not inflammation is going to be a major factor.
I was just reading Outlander by Diana Gabaldon and one of her characters has the short stature and disablity of Toulouse-Lautrec syndrome. I literally ran to my computer, because I am particularly interested in diseases of cartilage and bone. Since TLS is a genetic disease, I checked the NCBI Online Mendelian Inheritance in Man (OMIM) site and found that the genetic defect is in the cathepsin K gene. Cathepsin K is a protease similar to papain, which is intimately involved in many different facets of development, as well as cartilage and bone production. The cells that degrade cartilage to remodel bone, osteoclasts, use cathepsin K to degrade collagen.
I found a structure for cathepsin K bound to chondroitin sulfate. The structure looked all wrong, based on my prejudices -- the sugars of the polysaccharide should have been bound to the basic amino acids or to surface aromatic amino acids. The accompanying amino acid sequence told the whole story:
There were two triplets of basic amino acids (R, arginine or K, lysine), indicative of internalization and strong heparin binding. I performed a quick literature search for heparin binding and internalization and found a reference that confirmed my hunches (note the title):
Nascimento FD, Rizzi CC, Nantes IL, Stefe I, Turk B, Carmona AK, Nader HB, Juliano L, Tersariol IL. Cathepsin K binds to cell surface heparan sulfate proteoglycans. Arch Biochem Biophys. 2005 Apr 15;436(2):323-32.
The article demonstrated that cathepsin K bound only to the surface of cells that produced heparin sulfate and was internalized only by heparin-producing cells. Moreover, cathepsin K changed shape as it bound to heparin, but not to chondroitin sulfate.
This story underscores the predictive power of simple generalizations derived from the dominating interactions between heparin and proteins. Heparin-binding domains, because of their positive charges, stay on the surface of the protein, don’t tend to fold well into helices or other secondary structures and are readily recognized in amino acid sequences of proteins. Stronger heparin-binding domains involved in internalization or transport into nuclei are even more stereotyped as triplets or quadruplets, respectively, of basic amino acids.
There are some complicating special cases involving basic amino acids, since these amino acids are also involved in glycosylation, nucleic acid binding, inositol phosphate interactions, phospholipid interactions, protein folding/chaperone binding, and protease action, but the generalizations outlined here provide a starting point for exploring the exciting area of heparin binding.
Knowing just a few typical patterns, you can just look at a protein sequence and amaze people by telling them that they should be able to purify their protein on heparin Sepharose! You can also point and gasp at the fact that in the early 1990’s in China the bird flu hemagglutinin picked up a new sequence with a quartet of four basic amino acids. When I saw that I called the CDC and explained the new cell receptor! It still has me scared -- am I the first one to notice the potential for a pandemic much more severe than the 1918 Spanish flu?
The power of simple sequence pattern analysis in predicting protein behavior is illustrated in the case of Cathepsin K, a papain-like cysteine protease, involved in many degenerative diseases, bone development and Pycnodysostosis (Toulouse-Lautrec syndrome.) Triplets of basic amino acids are typical of heparin binding proteins that are internalized.
I admit that I am obsessed with inflammation and heparin. My daughters automatically yell out “Give him heparin!” when a patient on ER has a severe migraine attack. They think it is a good joke until the savvy doc reveals the latest approach and actually injects heparin with satisfying results. Heparin and inflammation are intimately involved and I predict that blood tests that determine the quality and quantity of protein-bound heparin, will ultimately be used as measures of chronic inflammation, as well as revealing a variety of diseases.
I have a habit of examining the molecular basis of diseases that I encounter on TV, in newspapers or in books. Wikipedia is my first source, followed by the National Center for Biotechnology Information (NCBI). As soon as I find the genes/proteins involved, I check to see if the structures has been determined by X-ray crystallography or NMR, and then I look at the amino acid sequence. I check for pairs or triplets of basic amino acids. Invariably the pairs are matched with a neighboring basic amino acid, and that is a putative heparin-binding domain. Triplets almost always indicate secreted proteins that are brought back into cells dependent on strong affinity for recycled heparan sulfate proteoglycans. Within minutes of hearing about a new disease, I usually know something about the molecules involved and particularly whether or not inflammation is going to be a major factor.
I was just reading Outlander by Diana Gabaldon and one of her characters has the short stature and disablity of Toulouse-Lautrec syndrome. I literally ran to my computer, because I am particularly interested in diseases of cartilage and bone. Since TLS is a genetic disease, I checked the NCBI Online Mendelian Inheritance in Man (OMIM) site and found that the genetic defect is in the cathepsin K gene. Cathepsin K is a protease similar to papain, which is intimately involved in many different facets of development, as well as cartilage and bone production. The cells that degrade cartilage to remodel bone, osteoclasts, use cathepsin K to degrade collagen.I found a structure for cathepsin K bound to chondroitin sulfate. The structure looked all wrong, based on my prejudices -- the sugars of the polysaccharide should have been bound to the basic amino acids or to surface aromatic amino acids. The accompanying amino acid sequence told the whole story:
---DYRKKGYVTPVKNQGQCGSCWAFSSVGALEGQLKKKT---
There were two triplets of basic amino acids (R, arginine or K, lysine), indicative of internalization and strong heparin binding. I performed a quick literature search for heparin binding and internalization and found a reference that confirmed my hunches (note the title):
Nascimento FD, Rizzi CC, Nantes IL, Stefe I, Turk B, Carmona AK, Nader HB, Juliano L, Tersariol IL. Cathepsin K binds to cell surface heparan sulfate proteoglycans. Arch Biochem Biophys. 2005 Apr 15;436(2):323-32.
The article demonstrated that cathepsin K bound only to the surface of cells that produced heparin sulfate and was internalized only by heparin-producing cells. Moreover, cathepsin K changed shape as it bound to heparin, but not to chondroitin sulfate.
This story underscores the predictive power of simple generalizations derived from the dominating interactions between heparin and proteins. Heparin-binding domains, because of their positive charges, stay on the surface of the protein, don’t tend to fold well into helices or other secondary structures and are readily recognized in amino acid sequences of proteins. Stronger heparin-binding domains involved in internalization or transport into nuclei are even more stereotyped as triplets or quadruplets, respectively, of basic amino acids.
There are some complicating special cases involving basic amino acids, since these amino acids are also involved in glycosylation, nucleic acid binding, inositol phosphate interactions, phospholipid interactions, protein folding/chaperone binding, and protease action, but the generalizations outlined here provide a starting point for exploring the exciting area of heparin binding.
Knowing just a few typical patterns, you can just look at a protein sequence and amaze people by telling them that they should be able to purify their protein on heparin Sepharose! You can also point and gasp at the fact that in the early 1990’s in China the bird flu hemagglutinin picked up a new sequence with a quartet of four basic amino acids. When I saw that I called the CDC and explained the new cell receptor! It still has me scared -- am I the first one to notice the potential for a pandemic much more severe than the 1918 Spanish flu?
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