Thyroid and glutamate connection

Iritu1021

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This confirms what I've hypothesized before based on my experience - that low T3 and/or T3 sensitivity are related to abnormalities of glutamatergic signaling. The body will likely raise T3 on its own once glutamate or other neurotransmitter imbalance is addressed and it's safe for the nerve cells to do so. Thus, in CFS one may regard low t3 syndrome as a symptom of neurotransmitter dysfunction rather than its cause.

https://www.ncbi.nlm.nih.gov/pubmed/18065155

Nongenomic regulation of glutamatergic neurotransmission in hippocampus by thyroid hormones.
Losi G1, Garzon G, Puia G.
Author information

Abstract
Thyroid hormones (THs) are well known for their genomic effects but recently attention has focused also on their nongenomic actions as rapid modulators of membrane receptors. Here we show that thyroxine (T4) and 3,3',5'-l-triiodothyronine (T3) rapidly decrease N-methyl-d-aspartate (NMDA)-evoked currents in rat hippocampal cultures with potency in the micromolar range. The effect is not mediated by glutamate or glycine binding sites as an increase in agonist or glycine concentration does not alter TH potencies. Furthermore THs' effect on NMDAreceptors is independent of voltage and of subunit composition. The mechanism of THs' antagonistic effect does not involve PKC phosphorylation of NMDA receptors since neither blocking nor stimulating PKC changed THs' modulation. T3, but not T4, inhibits also kainate-evoked currents in hippocampal neurons in culture. In hippocampal pyramidal neurons in slice, T3, but not T4, significantly reduced the frequency of miniature excitatory postsynaptic currents (mEPSCs) without affecting their amplitude and decay. In cultured rat cortical neurons THs prevented glutamate-induced neuronal death at concentrations similar to those effective on glutamatergic receptors. Taken together our data show for the first time that THs can rapidly affect ionotropic glutamatergic receptors in hippocampal neurons, an effect that could have an important role in their modulation of brain function in physiological and pathological states.


@pattismith @drob31 @BadBadBear @debored13
 

pattismith

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thank you for tagging me, this is an amazing paper; i will need to work a lot on it to understand, but I really feel motivated!

I already came to the same conclusion that my Hypothalamus/pituitary sensitivity to T3 is not the cause of my illness ( it may worsen the clinical outcome but not more than that) and i was able to stopped my T3 intake a few weeks ago, when I found some help from other supplements.:thumbsup:
 

pattismith

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I had transient good effect from T3 + caffeine, it was very quick so I hypothetized it was a non genomic effect.


Caffeine is an adenosine receptor antagonist, but I never had a good effect from caffeine alone.


I wonder if the benefit I have from Inosine + caffeine could be related to the blockade of NMDA receptors...

Inosine is an adenosine receptor agonist. This picture shows A1R activation has NMDA inhibitory effect, (while A2R antagonist prevent motor inhibition). This could work if Inosine has much affinity to A1R than caffeine, which I ignore...


 
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that low T3 and/or T3 sensitivity are related to abnormalities of glutamatergic signaling.
@Iritu1021
This is absolutely gob-smackingly fascinating, thank you so much for posting it ..... I've had a helluva time trying to explain to myself (and others) why I firmly believe that there's a connection between glutamate reactions and ME/CFS, and you've just given me a major foot-up on this mystery .....

Thank you thankyou thank you !!!
 
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Glutamate drug coming down the chute. Looks to be doing well in existing clinical studies, and no side effects :thumbsup:
@Belbyr

I'd be more enthusiastic if that wasn't what they said about Prozac and every ensuing generation of SSRIs ....

I'll wait to try it til there's more input about side effects etc available .... it's not that I don't trust them entirely, it's that I don't trust them at all .....they always come up with the equivalent of a giant flamethrower to light a candle .....it does finally lite the wick, but the candle is melted into a little pool of hot wax, soooooooo ......
 
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Karl Morten in his recent NZ presentation showed a 6 fold change in glutamate in patients
@wigglethemouse
Excellent, and thank you so much for contributing another piece to the puzzle of what I've suspected for so long and haven't been able to prove or find supportive input for. No matter how much I wiggled the mouse. :):):thumbsup: ..... like you've never had to endure that sad little attempt at word play ..... apologies ..... tried, couldn't stop myself ...:nervous:
 
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Iritu1021

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thank you for tagging me, this is an amazing paper; i will need to work a lot on it to understand, but I really feel motivated!

I already came to the same conclusion that my Hypothalamus/pituitary sensitivity to T3 is not the cause of my illness ( it may worsen the clinical outcome but not more than that) and i was able to stopped my T3 intake a few weeks ago, when I found some help from other supplements.:thumbsup:
@pattismith I was browsing through Goldstein's book again two days ago and he mentions there that both dipyridamole and adenosine are involved in the protection from glutamate neurotoxicity.

I also found a recent review on mechanisms of depression and apparently glutamate rather than monoamines are involved in mood disorders according to the latest science. The reason why monoaminergic theories still prevail is because the monoamines (e.g serotonin and glutamate) were discovered in 1950s and glutamate only in 1980 so it sent the scientists down the wrong track. But apparently glutamatergic synapses comprise 80 % of all synapses in the brain and almost all of the rest is GABAergic synapses.
 
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But apparently glutamatergic synapses comprise 80 % of all synapses in the brain and almost all of the rest is GABAergic synapses.
@Iritu1021
And in a battle between the two for resources, glutamatergic synapses will win almost every time, leaving the patient twisting in the wind and gasping for relief ....

I suppose for survival, the parasympathetic 'rest and digest' of GABA does nothing to get you out of the path of saber tooth tigers, but it does seem really unfair ... long, soulful sighhh
 

Iritu1021

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@Iritu1021
And in a battle between the two for resources, glutamatergic synapses will win almost every time, leaving the patient twisting in the wind and gasping for relief ....

I suppose for survival, the parasympathetic 'rest and digest' of GABA does nothing to get you out of the path of saber tooth tigers, but it does seem really unfair ... long, soulful sighhh
It's not as simple as too much glutamate though... there are stages or bipolar nature to this problem in my experience. Both too low and too high glutamate is bad. I went through an excitototoxic stage illness, and now I'm in my late stage where my glutamate synapses have "pruned" over time either due to overworking or as a protective mechanism adapted on a genetic level... of course if I try to raise glutamate it's very easy to develop toxicity again... what I need now is to raise my glutamatergic transmission while preventing glutamate toxicity,
 
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It's not as simple as too much glutamate though...
Both too low and too high glutamate is bad
Completely agree .. that's what's so endlessly frustrating about dealing with this ...

what I need now is to raise my glutamatergic transmission while preventing glutamate toxicity,
That's my Holy Grail, I think everyone's Holy Grail with this complex issue .... I've managed to contain its anxiety producing effect and possibly its potential for uncontrolled damage, but like you, am constantly teetering on the edge. If you come up with anything, please, oh please, post here, yes?

The diagrams are terrific, and thank you for posting them. Will parse them out gradually, since my background in bio chem is, shall we say, uhhhh.... limited :confused: :):)
 

Iritu1021

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I am currently trying taurine, sarcosine, NAC, and microdosing T3 again per Blanchard protocol (it’s on my blog). Red Ginseng (at least the real stuff that you boil) has a nice boosting effect on my glutamate too via 5НТ2А receptor which dimerizes with NMDA.
I’ll let you guys know how it goes. Taurine has a nice calming effect on me. It acts on GAD enzyme that converts glutamate to GABA.
My T3 got low again after I stopped lithium orotate and lowered my T4 dose. T3 microdosing (less than 1 mcg in slow release form) seems to turn the switch on in my brain and provides an immediate relief of depression while regular tiny doses of T3 or NDT make me feel worse. There clearly is a biphasic mode of action with T3 in regard to glutamate. I’ve been talking about this phenomenon both here and on my blog for a while now...
 
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There clearly is a biphasic mode of action with T3 in regard to glutamate. I’ve been talking about this phenomenon both here and on my blog for a while now...
@Iritu1021
Thank you so much for the update ..... have tried a few of them in the past but had negative reactions. However, that was before I was able to pretty much stabilize, and will now add them on my list of Try Soon's ... meaning, when I get up the courage.

And thank you for mentioning your blog, will be checking it out later today ..... I'm assuming that's it in your signature, yes?
 

Iritu1021

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@Iritu1021
Thank you so much for the update ..... have tried a few of them in the past but had negative reactions. However, that was before I was able to pretty much stabilize, and will now add them on my list of Try Soon's ... meaning, when I get up the courage.

And thank you for mentioning your blog, will be checking it out later today ..... I'm assuming that's it in your signature, yes?
Yes, that's the one - www.chronicfatiguediagnosis.com

Yes, the reactions always seem to be changing depending on my baseline status so previous responses are not indicative. Also, things often produce different effects in combination, and a lot of time when there is a partial benefit, it's worth trying to troubleshoot the side effects rather than stopping because I don't think we'll ever find the one perfect drug to fix all our interconnected neurological issues. In psychiatry, patients with treatment-resistant depression are often on an average combination of 4-5 drugs plus supplements.

For example, T3 gives me mental clarity and energy but it worsens my POTS, but I'm pretty sure it's because my NTs are too low right now to handle an increased metabolic rate. However, since the dose is so low (I take 0.3 mcg SR), I can likely correct it by increasing either NE or Ach with supplements or reuptake inhibitors, and if that doesn't work I'll try modulating my NMDA receptor.