Removing Glutamate from Brain with GOT/Oxaloacetate?

[Hip]

Any thoughts on Campral for glutamate lowering purposes?

Do you have any refs for its glutamate lowering action?

 

[Hip]

Hi Hip,

The last source you listed is a chemical supplier. Do you have any experience ordering from these types of companies?

I always wondered how they operated (legally), since they seem to sell pharmaceuticals as well (although at exorbitant prices.)

Yes I do. Some chemical suppliers are happy to sell (non-restricted) chemicals to individuals; others have rules such that they will only sell to companies. I am not sure what rules the above chemical supplier operates by.

 

[Valentijn]

Two people on that thread said they had near complete (but temporary) remission from their ME/CFS neurological symptoms (brain fog, etc) within a day or so of having injections / IV of the antibiotic Rocephin (ceftriaxone). This made very curious, and after a bit of research, I found out that Rocephin potently boosts gene expression of the brain's glutamate transporter EAAT2, which is the main glutamate transporter, responsible for clearing the bulk (90%) of the excess glutamate from the brain. This study found Rocephin increased glutamate transporter EAAT2 expression by 3-fold.

My theory is that these two patients got temporary remission from ME/CFS neurological symptoms due to Rocephin significantly ramping up the glutamate transporters. I am going to be trying Rocephin injections myself soon, to see if I can replicate this result.

I also had good effects starting about 1 week after finishing Rocephin, prior to starting on another antibiotic. My cognitive issues are also gone now, aside from during crashes. No pain or difficulty from concentrating for a while now.

I took a quick look at the EAAT2 (SLC1A2) gene for 31 patients and controls that I have full data for. Purple boxes indicate 0 - 1% prevalence of the genotype in the general population, red is 1 - 2.5%, orange is 2.5 - 5%, and yellow in 5-10%. Click on the image to see a bigger version.

So basically we have quite a few more of the rarest genotypes (0 - 2.5% prevalence), as a group, compared to the controls. My own results for these SNPs are pretty normal (I'm P7), though I am heterozygous for a few of the rarer ones that are more common in the ME patients.

 

[Ema]

Great info, @Valentijn.

Looks like I'm pretty red. 3 of them if I remember my number correctly!

 

[Valentijn]

Great info, @Valentijn.

Looks like I'm pretty red. 3 of them if I remember my number correctly!

You've got a new number now that the list is expanded! I'll PM you

 

[Ema]

Do you have any refs for its glutamate lowering action?

It looks like they aren't sure exactly how it works...or even if it works if this most recent article I found is any indication. I haven't delved into it fully but have just seen it mentioned on a few doctor websites as a possible treatment for benzo withdrawal.

However, if it *is* just the calcium having an effect, I'm confused as I thought calcium supps were to be avoided in benzo withdrawal. But I'm not 100% convinced that taking calcium as a supplement would have an effect on the calcium channels. Maybe, maybe not. I'll pull the new article and see if that helps explain anything.

Neuropsychopharmacology (2014) 39, 783–791; doi:10.1038/npp.2013.264; published online 15 January 2014

Acamprosate Produces Its Anti-Relapse Effects Via Calcium
Rainer Spanagel1,5, Valentina Vengeliene1,5, Bernd Jandeleit2,5, Wolf-Nicolas Fischer2, Kent Grindstaff2, Xuexiang Zhang2, Mark A Gallop2, Elena V Krstew3, Andrew J Lawrence3 and Falk Kiefer4

1. 1Institute of Psychopharmacology, Central Institute of Mental Health, University of Heidelberg, Medical Faculty Mannheim, Mannheim, Germany
2. 2XenoPort, Inc., Santa Clara, CA, USA
3. 3Florey Institute of Neuroscience & Mental Health, University of Melbourne, Melbourne, Australia
4. 4Department of Addictive Behavior and Addiction Medicine, Central Institute for Mental Health, Mannheim, Germany

Correspondence: Professor R Spanagel, Institute of Psychopharmacology, Central Institute for Mental Health, University of Heidelberg, Medical Faculty Mannheim, Square J5, Mannheim D-68159, Germany, Tel: +49 621 1703 6251, Fax: +49 621 1703 6255, E-mail: rainer.spanagel@zi-mannheim.de

5These authors contributed equally to this work.

Received 28 February 2013; Revised 16 September 2013; Accepted 17 September 2013
Accepted article preview online 30 September 2013; Advance online publication 15 January 2014

Topof page
Abstract
Alcoholism is one of the most prevalent neuropsychiatric diseases, having an enormous health and socioeconomic impact. Along with a few other medications, acamprosate (Campral—calcium-bis (N-acetylhomotaurinate)) is clinically used in many countries for relapse prevention. Although there is accumulated evidence suggesting that acamprosate interferes with the glutamate system, the molecular mode of action still remains undefined. Here we show that acamprosate does not interact with proposed glutamate receptor mechanisms. In particular, acamprosate does not interact with NMDA receptors or metabotropic glutamate receptor group I. In three different preclinical animal models of either excessive alcohol drinking, alcohol-seeking, or relapse-like drinking behavior, we demonstrate that N-acetylhomotaurinate by itself is not an active psychotropic molecule. Hence, the sodium salt of N-acetylhomotaurinate (i) is ineffective in alcohol-preferring rats to reduce operant responding for ethanol, (ii) is ineffective in alcohol-seeking rats in a cue-induced reinstatement paradigm, (iii) and is ineffective in rats with an alcohol deprivation effect. Surprisingly, calcium salts produce acamprosate-like effects in all three animal models. We conclude that calcium is the active moiety of acamprosate. Indeed, when translating these findings to the human situation, we found that patients with high plasma calcium levels due to acamprosate treatment showed better primary efficacy parameters such as time to relapse and cumulative abstinence. We conclude that N-acetylhomotaurinate is a biologically inactive molecule and that the effects of acamprosate described in more than 450 published original investigations and clinical trials and 1.5 million treated patients can possibly be attributed to calcium.

According to Wikipedia, it is a positive allosteric modulator of GABA-a, an NMDA antagonist, and a glutamate antagonist.

http://en.wikipedia.org/wiki/Acamprosate

Basically no one seems to know how it works, or even *if* it works, but it's been used in Europe for quite some time and is thought to rebalance the glutamate/GABA system by affecting the receptors and may help to prevent PAWS. The side effects look kind of brutal though (about the same as what they are meant to treat!).

ETA:

Here's a little more on the proposed mechanism of action in alcohol withdrawal.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2853976/

 

[Hip]

I took a quick look at the EAAT2 (SLC1A2) gene for 31 patients and controls that I have full data for. .... So basically we have quite a few more of the rarest genotypes (0 - 2.5% prevalence), as a group, compared to the controls.

That's very interesting Valentijn. So although there's not as yet research available to indicate what these various SNPs in the EAAT2 gene do, your data says that ME/CFS patients have more of the rarest mutations than healthy controls.

It would certainly be interesting to see some studies looking into EAAT2 functioning in ME/CFS patients.

 

[Ema]

By the way, have you seen this thread, Ema: Rocephin shots

Two people on that thread said they had near complete (but temporary) remission from their ME/CFS neurological symptoms (brain fog, etc) within a day or so of having injections / IV of the antibiotic Rocephin (ceftriaxone). This made me very curious, and after a bit of research, I found out that Rocephin potently boosts gene expression of the brain's glutamate transporter EAAT2, which is the main glutamate transporter, responsible for clearing the bulk (90%) of the excess glutamate from the brain. This study found Rocephin increased glutamate transporter EAAT2 expression by 3-fold.

My theory is that these two patients got temporary remission from ME/CFS neurological symptoms due to Rocephin significantly ramping up the glutamate transporters. I am going to be trying Rocephin injections myself soon, to see if I can replicate this result.

@Hip, I wonder if it is only Rocephin or if other cephalosporins have this effect on glutamate transporters. Have you looked into this at all?

 

[maryb]

@Valentijn
would you know where would I be on that list? and what it means?

 

[Valentijn]

@Valentijn
would you know where would I be on that list? and what it means?

Sent it via conversation!

 

[Hip]

@Hip, I wonder if it is only Rocephin or if other cephalosporins have this effect on glutamate transporters. Have you looked into this at all?

Yes I did. It has been found that many beta-lactam antibiotics will increase the expression of the EAAT2 glutamate transporter. In this study:

Role of Excitatory Amino Acid Transporter-2 (EAAT2) and Glutamate in Neurodegeneration: Opportunities for Developing Novel Therapeutics

the authors say:

Screening of approximately 1,040 FDA-approved compounds and nutritionals led to the discovery that many β-lactam antibiotics are transcriptional activators of EAAT2 resulting in increased EAAT2 protein levels.

Fifteen different β-lactam antibiotics were able to stimulate EAAT2 protein expression by more than two-fold. This increased expression of EAAT2 protein was detected as early as 48 h after drug treatment.

CEF [ceftriaxone] treatment in vitro and in vivo resulted in a 3-fold increase of EAAT2 protein expression levels and a comparable increase in EAAT2 transporter activity.

The human EAAT2 promoter was significantly activated by CEF [ceftriaxone], amoxicillin and dibutyryl cyclic AMP.

So another option might be to take amoxicillin orally, which would be easier than Rocephin (ceftriaxone) injections. I already checked the toxicity profile of amoxicillin, and it is fairly benign: the maximum daily dose is of amoxicillin is around 4 to 6 gram (given in divided doses).

Though the above study indicates that Rocephin is more potent, with its 3-fold increase of EAAT2. They don't mention the precise potency of amoxicillin, but from the above-quoted statements I am guessing it is somewhere between 2-fold and 3-fold.

 

[Ema]

Just my luck to have penicillin allergy. I seem to do ok (knock wood) with the later generation cephalosporins but I know I can't take amoxicillin. Boo. But maybe one of the others with the oxaloacetate will do the trick.

I haven't noticed anything from the oxaloacetate yet - good or bad. I'm thinking two doses (if not three) might be better. But expensive...

 

[Hip]

I came across a couple of studies (here and here) which found that subcutaneous administration of Rocephin is a feasible possibility.

This would make self-administration easier, compared to intravenous injection or infusion. I am quite confident in performing subcutaneous injections into my belly, having done this for various medications (like Nexavir), but I would not feel confident doing intravenous.

You do unfortunately get reduced Rocephin bioavailability if you use the subcutaneous route, though. The cited study found that the subcutaneous bioavailability of Rocephin was 39%, compared to 85% for intramuscular.

 

[Hip]

I seem to do ok (knock wood) with the later generation cephalosporins but I know I can't take amoxicillin.

The study I quoted above mentions that there are 15 different beta-lactam antibiotics which stimulate EAAT2 expression by more than two-fold; but unfortunately it does not list them. Some of these 15 might be cephalosporins, and thus possibly OK for you.

That study cites another study, though, namely: Beta-lactam antibiotics offer neuroprotection by increasing glutamate transporter expression, which I think may list these 15 beta-lactam antibiotics (I think this is the source study for the info). So if you can get hold of the full paper, you should be able to get that list.

 

[maryb]

The study I quoted above mentions that there are 15 different beta-lactam antibiotics which stimulate EAAT2 expression by more than two-fold; but unfortunately it does not list them. Some of these 15 might be cephalosporins, and thus possibly OK for you.

That study cites another study, though, namely: Beta-lactam antibiotics offer neuroprotection by increasing glutamate transporter expression, which I think may list these 15 beta-lactam antibiotics (I think this is the source study for the info). So if you can get hold of the full paper, you should be able to get that list.

Be interested in knowing which of the Beta-lactam antibiotics?

 

[Ema]

Be interested in knowing which of the Beta-lactam antibiotics?

I'm going to order up the paper @Hip mentioned and see what we can find...

 

[Ema]

There's no complete list unfortunately that I could find on a brief scan.

If you want a copy of the article, PM me.

 

[Hip]

@Ema: Another approach you might consider taking is using NMDA receptor antagonists to block the action of glutamate on the NMDA receptor.

Magnesium is a potent NMDA receptor antagonist, and transdermal magnesium is a good way of getting high doses of magnesium into the body for this purpose. (The easy-to-do transdermal magnesium technique I use is detailed here).


Interestingly, a study has shown that taking NMDA receptor antagonists with benzodiazepines can help prevent the tolerance and withdrawal symptoms in the first place:

Effect of NMDA antagonists on rapid tolerance to benzodiazepines


And AMPA receptor antagonists may also help prevent tolerance to and dependence on benzodiazepines:

Diazepam dependence prevented by glutamate antagonists

 

[LisaMaryT]

Dr. Blaylock who is mentioned in other threads on this site that I have not read yet, the author of Excitotoxins: The Taste That Kills, said that pyruvate protects your brain against glutamate and has other benefits. http://www.naturalnews.com/035555_Russell_Blaylock_interview_excitotoxins.html. I have had lifelong health challenges and have spent years on special diets,etc and recently discovered eating too much chicken stock was contributing to my health challenges and am using this product to help regain balance. http://www.nutricology.com/Calcium-Pyruvate-90-Vegetarian-Caps-p-16440.html. I found DogtorJ today thanks to this thread and these are some of the links that got me here. http://www.holistichelp.net/blog/how-to-increase-gaba-and-balance-glutamate/, http://www.dramyyasko.com/wp-conten...of-Excitotoxins-in-Autistic-Type-Behavior.pdf, http://www.biodynamicwellness.com/stock-vs-broth-confused/

 

[Ema]

Calcium pyruvate does look very interesting. This article says it protects the mitochondria against glutamate induced excitotoxicity.

Unfortunately it also says that the dosing is too high for clinical use and it can't reverse damage already done.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3995922/