• Welcome to Phoenix Rising!

    Created in 2008, Phoenix Rising is the largest and oldest forum dedicated to furthering the understanding of and finding treatments for complex chronic illnesses such as chronic fatigue syndrome (ME/CFS), fibromyalgia (FM), long COVID, postural orthostatic tachycardia syndrome (POTS), mast cell activation syndrome (MCAS), and allied diseases.

    To become a member, simply click the Register button at the top right.

FROM MOOD DISORDERS TO MCS: A NEUROINFLAMMATORY MODEL

Lotus97

Senior Member
Messages
2,041
Location
United States
Rich thought one of the causes glutamate induced excitotoxicity was due to low glutathione in the astrocytes.
Quite a few PWMEs who have tried the methylation protocol have reported that they have experienced an increase in symptoms associated with excitotoxicity when they began (anxiety, insomnia, nervousness). In the past, I have suggested trying acetyl glutathione or liposomal glutathione to counter this. One or two people reported that they thought this helped them.

Now I would like to suggest something else that I think would help with this, which is less expensive: L-cystine. Note here that I do mean L-cystine, not L-cysteine. (Cystine is the oxidized form of cysteine, consisting of two cysteine molecules bound together by a disulfide bond.) Douglas Laboratories is one producer of L-cystine, and there are at least a couple of suppliers of it
on the internet advertising 60 capsules, 500 mg each, for $16.50. I would suggest starting with a dosage of 500 mg and increasing to as much as 1,500 mg, depending on the response. L-cystine should not be taken by people who have a tendency to develop cystine kidney stones, or people who suspect that they have a high body burden of mercury, because L-cystine may move mercury around. And as always, I recommend working with a physician while on this protocol.

Here is the rationale:

I believe that the increase in excitotoxicity results from a further drop in the glutathione levels in the astrocytes (helper cells) in the brain, when the protocol is begun. (We know
from the recent MRS measurements of Shungu et al. that glutathione is already somewhat depleted in the brain in ME/CFS.) The further drop in glutathione lowers the production of ATP by the mitochondria of these cells, and they then have less energy for pumping glutamate out of the synapses and recycling it. When glutamate builds up, it overexcites the NMDA receptors, and that produces excitotoxicity.

If this is true, then it would seem that we may be able to lower the excitotoxicity if we can support the glutathione levels in the astrocytes as this protocol is begun.

According to the Dringen model, the astrocytes make their glutathione using cystine as their source of cysteine. Cystine is obtained from the blood, and is able to pass through the blood-brain barrier.

How does cystine normally get into the blood? The liver produces glutathione from the constituent amino acids that it receives from the diet via the intestine and the portal vein blood flow. The liver exports some of its glutathione to the circulating blood, and enzymes break down the glutathione into its constituent amino acids. The cysteine is mostly oxidized to cystine, and some of this is taken up from the blood by the brain.

When the methylation protocol is begun, the activity of the methionine synthase enzyme in the liver is increased by supplementing B12 and folate forms. This causes more of the homocysteine to be converted to methionine, so less is available to support synthesis of glutathione. One result of this is that the cystine level in the blood goes down, so that less of it is available to the brain.

It would therefore seem that if L-cystine were supplemented, it would augment the cystine in the blood and increase the supply available to the brain, and hence to the astrocytes. Hopefully, this would raise the glutathione levels in these cells, and increase their ability to remove glutamate from the synapses, lowering the excitotoxicity. Ingested cystine is not metabolized significantly by the liver, because it does not import cystine readily.

If anybody decides to try this, I would be interested to hear the results, whatever they turn out to be. Thanks.

Best regards,

Rich
I think this is the study Rich is referring to in regards to decreased glutathione measured in the brain of CFS/ME
http://www.ncbi.nlm.nih.gov/pubmed/22281935
Increased ventricular lactate in chronic fatigue syndrome. III. Relationships to cortical glutathione and clinical symptoms implicate oxidative stress in disorder pathophysiology.
Abstract
Chronic fatigue syndrome (CFS) is a complex illness, which is often misdiagnosed as a psychiatric illness. In two previous reports, using (1)H MRSI, we found significantly higher levels of ventricular cerebrospinal fluid (CSF) lactate in patients with CFS relative to those with generalized anxiety disorder and healthy volunteers (HV), but not relative to those with major depressive disorder (MDD). In this third independent cross-sectional neuroimaging study, we investigated a pathophysiological model which postulated that elevations of CSF lactate in patients with CFS might be caused by increased oxidative stress, cerebral hypoperfusion and/or secondary mitochondrial dysfunction. Fifteen patients with CFS, 15 with MDD and 13 HVs were studied using the following modalities: (i) (1)H MRSI to measure CSF lactate; (ii) single-voxel (1)H MRS to measure levels of cortical glutathione (GSH) as a marker of antioxidant capacity; (iii) arterial spin labeling (ASL) MRI to measure regional cerebral blood flow (rCBF); and (iv) (31)P MRSI to measure brain high-energy phosphates as objective indices of mitochondrial dysfunction. We found elevated ventricular lactate and decreased GSH in patients with CFS and MDD relative to HVs. GSH did not differ significantly between the two patient groups. In addition, we found lower rCBF in the left anterior cingulate cortex and the right lingual gyrus in patients with CFS relative to HVs, but rCBF did not differ between those with CFS and MDD. We found no differences between the three groups in terms of any high-energy phosphate metabolites. In exploratory correlation analyses, we found that levels of ventricular lactate and cortical GSH were inversely correlated, and significantly associated with several key indices of physical health and disability. Collectively, the results of this third independent study support a pathophysiological model of CFS in which increased oxidative stress may play a key role in CFS etiopathophysiology.
 
Messages
3
Location
Lincoln, NE, US
I spent a fair amount of time this winter researching the common factors between all of the diagnoses I have ever received, it's a depressing whopper of a list, looking for common factors. Increased glutamate levels were a factor in many of them; including fibromyalgia, bipolar, PTSD, depression, generalized anxiety disorder, IBS, restless leg syndrome and migraines.

One of the simple things that may decrease glutamate is dextromethorphan. I say may because for it to have this action requires a certain enzyme which 16% of the population does not have. There is a drug company that recently patented a drug that is a combination of dextromethorpan and quinidine, as the quinidine overrides this deficit. The drug has been FDA approved for, and is currently being marketed for a rare condition related to alzheimers. However, it is being studied for a multitude of conditions. For the life of me I cannot remember the drug name or the company, go figure. :)

My own trial with dxm yielded no results. Although, the first 4 days while I was using one brand I had a total disappearance of the awful depression that plagued me all winter, and an increase in energy. However, after that I had to switch brands because of the ridiculous cost and no longer saw any benefits.

Cucurmin has also been shown to lower glutamate, at least in rat brains. Gotta love research.

I started a new rx for bipolar 12 days ago and have noticed that my activity and energy levels have increased sightly, hopefully it is not a fluke. It does prevent the release of glutamate, the brand name is Lamictal. However, the side effect profile mimics many of my CFS symptoms, so we'll see how it goes as I titrate up on the doseage.
 

Lotus97

Senior Member
Messages
2,041
Location
United States
One of the simple things that may decrease glutamate is dextromethorphan. I say may because for it to have this action requires a certain enzyme which 16% of the population does not have. There is a drug company that recently patented a drug that is a combination of dextromethorpan and quinidine, as the quinidine overrides this deficit. The drug has been FDA approved for, and is currently being marketed for a rare condition related to alzheimers. However, it is being studied for a multitude of conditions. For the life of me I cannot remember the drug name or the company, go figure. :)

My own trial with dxm yielded no results. Although, the first 4 days while I was using one brand I had a total disappearance of the awful depression that plagued me all winter, and an increase in energy. However, after that I had to switch brands because of the ridiculous cost and no longer saw any benefits.
Be careful with DXM. It's possible to overdose on that. Dextromethorphan is listed as an NMDA antagonist so I assume it would help with other excitotoxins besides glutamate (?)
 

Marco

Grrrrrrr!
Messages
2,386
Location
Near Cognac, France
I spent a fair amount of time this winter researching the common factors between all of the diagnoses I have ever received, it's a depressing whopper of a list, looking for common factors. Increased glutamate levels were a factor in many of them; including fibromyalgia, bipolar, PTSD, depression, generalized anxiety disorder, IBS, restless leg syndrome and migraines.

One of the simple things that may decrease glutamate is dextromethorphan. I say may because for it to have this action requires a certain enzyme which 16% of the population does not have. There is a drug company that recently patented a drug that is a combination of dextromethorpan and quinidine, as the quinidine overrides this deficit. The drug has been FDA approved for, and is currently being marketed for a rare condition related to alzheimers. However, it is being studied for a multitude of conditions. For the life of me I cannot remember the drug name or the company, go figure. :)

My own trial with dxm yielded no results. Although, the first 4 days while I was using one brand I had a total disappearance of the awful depression that plagued me all winter, and an increase in energy. However, after that I had to switch brands because of the ridiculous cost and no longer saw any benefits.

Cucurmin has also been shown to lower glutamate, at least in rat brains. Gotta love research.

I started a new rx for bipolar 12 days ago and have noticed that my activity and energy levels have increased sightly, hopefully it is not a fluke. It does prevent the release of glutamate, the brand name is Lamictal. However, the side effect profile mimics many of my CFS symptoms, so we'll see how it goes as I titrate up on the doseage.


That's a very familiar list of conditions Annabel!
 

Lotus97

Senior Member
Messages
2,041
Location
United States
Marco
You mentioned neuropathy in the article. What about the people who get relief from their symptoms by taking high doses of methylcobalamin? How does that fit in with this?
 

Marco

Grrrrrrr!
Messages
2,386
Location
Near Cognac, France
Marco
You mentioned neuropathy in the article. What about the people who get relief from their symptoms by taking high doses of methylcobalamin? How does that fit in with this?


Hi Lotus97

Methly B12 is protective against neuroinflammation both centrally (e.g; in Alzheimers) and peripherally (as with peripheral neuropathies)..
 

John H Wolfe

Senior Member
Messages
220
Location
London
Quite an article! Inclined to agree glutamate is involved in (one of) the core process(es) involve in ME/CFS, as I understand it e.g. as a Neural Hyper-Sensitivity Syndrome, as per the discussion in my hypothesis article relating to peripheral-central sensitisation and mitochondrial dysfunction:

Central terminals of the nociceptor release a host of signal molecules e.g. neuropeptides and the neurotransmitter glutamate; these act on specific spinal cord neuronal receptors, activating the phosphorylation receptors and channels, particularly the NMDA and AMPA receptors for glutamate

...

The detection (of ATP) activity of receptors on (ATP) channels determine the balance between glutamate and GABA production (nervous system excitation vs. inhibition). NMDA receptors detect glutamate and are found in the greatest abundance in the hippocampus,basal ganglia, and amygdala
 

Marco

Grrrrrrr!
Messages
2,386
Location
Near Cognac, France
Quite an article! Inclined to agree glutamate is involved in (one of) the core process(es) involve in ME/CFS, as I understand it e.g. as a Neural Hyper-Sensitivity Syndrome, as per the discussion in my hypothesis article relating to peripheral-central sensitisation and mitochondrial dysfunction:

Central terminals of the nociceptor release a host of signal molecules e.g. neuropeptides and the neurotransmitter glutamate; these act on specific spinal cord neuronal receptors, activating the phosphorylation receptors and channels, particularly the NMDA and AMPA receptors for glutamate

...

The detection (of ATP) activity of receptors on (ATP) channels determine the balance between glutamate and GABA production (nervous system excitation vs. inhibition). NMDA receptors detect glutamate and are found in the greatest abundance in the hippocampus,basal ganglia, and amygdala


Thanks John

Its not an isolated article but one in a series of 'blogs' that follows what I think is a logical sequence of inquiry as detailed in this thread :

http://forums.phoenixrising.me/inde...-tied-to-infections-autoimmune-disease.23782/
 
Messages
33
I also avoid MSG (monosodium glutamate) like the plague. This means eating home cooked unprocessed foods for the most part. Manufacturers use a ton of different names to hide it, and even "natural flavors" must be considered suspect.

There's an article on pubmed about MSG and fibro.
BACKGROUND:

Fibromyalgia is a common rheumatologic disorder that is often difficult to treat effectively.
CASE SUMMARY:

Four patients diagnosed with fibromyalgia syndrome for two to 17 years are described. All had undergone multiple treatment modalities with limited success. All had complete, or nearly complete, resolution of their symptoms within months after eliminating monosodium glutamate (MSG) or MSG plus aspartame from their diet. All patients were women with multiple comorbidities prior to elimination of MSG. All have had recurrence of symptoms whenever MSG is ingested.
DISCUSSION:

Excitotoxins are molecules, such as MSG and aspartate, that act as excitatory neurotransmitters, and can lead to neurotoxicity when used in excess. We propose that these four patients may represent a subset of fibromyalgia syndrome that is induced or exacerbated by excitotoxins or, alternatively, may comprise an excitotoxin syndrome that is similar to fibromyalgia. We suggest that identification of similar patients and research with larger numbers of patients must be performed before definitive conclusions can be made.
CONCLUSIONS:

The elimination of MSG and other excitotoxins from the diets of patients with fibromyalgia offers a benign treatment option that has the potential for dramatic results in a subset of patients.

Marco, I don't know if you're familiar with Dr. Jay Goldsteins theory, but it's largely based on NMDA (main glutamate receptor) receptor overactivity. You might find it interesting.[/QUOTE]
Hi
Intersesting about MSG. I a had a severe reaction to Asian Food last night. Severe Myoclonus and joint/muscle pain the next day. Anyone have more pain after MSG? I know about it being an Excitotoxin but the reaction I had was
so unusual. Inflamed my neck, low back and old injuries.