Hippocampal Gene Expression of Deiodinases 2 and 3 and Effects of 3,5-Diiodo-L-Thyronine T2 in Mouse Depression Paradigms

[helvella]

Another day, another post about a paper with an unpronounceable title!

This time about that mysterious substance T2 - into which both T3 and reverse T3 are converted.

If I said that I understood the paper I would be lying! I haven't even read it all. But as so often, I feel the need to shout from the rooftop that there are researchers out there finding out all sorts of new aspects of thyroid hormone metabolism and signalling.

Hopefully someone with a much deeper understanding might be able to summarise in nice short sentences for the likes of me. Please.

Biomed Res Int. 2013; 2013: 565218.

Published online 2013 December 10. doi: 10.1155/2013/565218

PMCID: PMC3872397

Hippocampal Gene Expression of Deiodinases 2 and 3 and Effects of 3,5-Diiodo-L-Thyronine T2 in Mouse Depression Paradigms

Natalyia Markova, 1 Anton Chernopiatko, 2 Careen A. Schroeter, 3 Dmitry Malin, 4 , 5 Aslan Kubatiev, 5 Sergey Bachurin, 1 João Costa-Nunes, 6 , 7 Harry M. W. Steinbusch, 6 and Tatyana Strekalova 3 , 6 , 7 ,*

Abstract

Central thyroid hormone signaling is important in brain function/dysfunction, including affective disorders and depression. In contrast to 3,3′,5-triiodo-L-thyronine (T3), the role of 3,5-diiodo-L-thyronine (T2), which until recently was considered an inactive metabolite of T3, has not been studied in these pathologies. However, both T3 and T2 stimulate mitochondrial respiration, a factor counteracting the pathogenesis of depressive disorder, but the cellular origins in the CNS, mechanisms, and kinetics of the cellular action for these two hormones are distinct and independent of each other. Here, Illumina and RT PCR assays showed that hippocampal gene expression of deiodinases 2 and 3, enzymes involved in thyroid hormone regulation, is increased in resilience to stress-induced depressive syndrome and after antidepressant treatment in mice that might suggest elevated T2 and T3 turnover in these phenotypes. In a separate experiment, bolus administration of T2 at the doses 750 and 1500 mcg/kg but not 250 mcg/kg in naive mice reduced immobility in a two-day tail suspension test in various settings without changing locomotion or anxiety. This demonstrates an antidepressant-like effect of T2 that could be exploited clinically. In a wider context, the current study suggests important central functions of T2, whose biological role only lately is becoming to be elucidated.

Entire paper available here:

ncbi.nlm.nih.gov/pmc/articl...

Rod

[Clutter]

Aha! I've wondered where T2 fits into the scheme of things. Deffo a read for tomorrow, though. Thank you

*wonders why the mice aren't on antidepressants?*

[shaws in reply to Clutter]

Maybe they're on levo instead.

[PinkNinja in reply to shaws]

Hahaha!

[shaws]

Hi Rod,

That's a good link which will probably have no notice taken of it by the medical profession.

Just goes to show that Mother Nature provides us with these important hormones, T4, T3, T2, T1 etc. and the BTA and RCoP

are insistent that we can get along with levo alone. No wonder so many still feel unwell and we've had a few posts recently connecting hypo and depression.

[sandi]

Please tell me the "tail suspension test" does not mean what it sounds like!!!! Eek!

[PinkNinja in reply to sandi]

research.psu.edu/arp/experi...

Poor mice

[sandi in reply to PinkNinja]

Thank you (I think!) for the link.

I don't know about it being depression, I think the mice might be sensible to stop trying! I sometimes wish I could stop banging my head against the brick wall of trying to sort out the thyroid issues and just have a rest.... oh, maybe I am depressed after all!

[helvella]

I am not sure that it does. After all, we have no idea how much T2 or T1 is in desiccated thyroid - I suspect that it is an absolutely infinitesimal amount, but I could be wrong. (At least some mentions of T2 and T1 in thyroid glands appears to confuse DIT and MIT with T2 and T1.) Also, no attempt is made to even to test for T2 and T1 in the production of desiccated thyroid so far as I am aware. So whatever might be there could vary dramatically.

On a simplistic "molecule counting" basis we would expect that every molecule of T3 we metabolise would result in a molecule of T2.

Also, it is often said that taking levothyroxine can result in elevated rT3. As rT3 also gets converted to T2, it doesn't seem impossible that T2 might actually be at least as high in those on levothyroxine-only.

Rod

[diogenes Remembering in reply to helvella]

Interesting study but not conclusive. The trouble is that extrapolating from mouse to man is littered with misleading conclusions. Eg mouse metabolism is far faster than man's, and might need more inputs from more thyroid factors including T2. The effect of T2 might be direct or indirect, ie synergistic with T3 (potentiating T3 activity at receptor level) or as a direct influence complementing T3. I'm sure T2 is doing something, but if it is as important in man as in mice/rats is still open. Antidepressive ideas are interesting though and need followup in humans if it is at all possible.

[PR4NOW in reply to diogenes]

Diogenes, as far as I can tell shrinks started experimenting with using T3 to augment treatment for depression in the 1980s. I think the problem was that they never gave them enough. In 2009 they had a trial where they did give enough and the results were pretty good. ncbi.nlm.nih.gov/pubmed/192... People on T3 usually suppress TSH and have high FT3, low FT4 which usually freaks doctors out.

I do not mean to suggest that thyroid will always fix depression but I bet it is involved more often than realized. If you read the early writings from the late 1800s and early 1900s when they didn't have tests and had to observe their patients, what they observed was everything from mild depression to frank insanity and everything in between including auditory and visual hallucinations and a lot of paranoia. PR

PS interesting link Rod, hopefully they will keep exploring.

[diogenes Remembering in reply to PR4NOW]

Re this link with depression the following is of interest:

Thyroid dysfunction in refractory depression: Implications for pathophysiology and treatment.

Howland, Robert H.

Journal of Clinical Psychiatry, Vol 54(2), Feb 1993, 47-54.

[PR4NOW in reply to diogenes]

"Fifty-two percent of patients with refractory depression in six clinical studies evidenced subclinical hypothyroidism (range, 29%-100%), which can be contrasted with a prevalence of approximately 8% to 17% in unselected populations of depressed patients."

One of the problems with these studies is always how did they determine that the patient is sub clinically hypothyroid.

"where a specific measure of thyroid function was used, such as thyroid indices, thyroid-releasing hormone stimulation, or basal metabolic rate."

They were looking at articles from 1970 to the present so "thyroid indices" could have been the PBI or 1st gen thru 3rd gen TSH as well as TRH and the BMR. Given that most testing only correlates with the clinical presentation of symptoms at the extremes, I just don't trust the numbers anymore to be anything but broad generalizations that are usually highly inaccurate. There is no apples to apples. I'll bet the percentage is actually higher than 8%-17%. Having experienced 'clinical depression' related to undiagnosed and untreated low thyroid, I can vouch for the fact that they are related. The docs of course wanted to give me ADs, but no thyroid because my blood tests were "normal", even though I have a 100 years of family history of thyroid problems. Of course I also have to admit that I am an outlier. PR

[PinkNinja in reply to PR4NOW]

That is very interesting about the experimenting on psychiatric patients. I was prescribed T3 before I was diagnosed hypothyroid (but after I started exhibiting symptoms) to treat a particularly resistant depression due to Schizo affective disorder (which was probably actually my thyroid) . I was prescribed 20mcg. This was before I was diagnosed hypothyroid but several years after I started exhibiting symptoms. It was nothing less than miraculous. I felt great physically and mentally, started running 10k races , was able to return to work and lost all the weight I had suddenly gained after always being skinny.

Once I was "cured" , the T3 was stopped and all my symptoms returned. A couple of years later I was finally diagnosed hypo and my GP felt T3 would be the sensible option given how well I was on it before. Another miraculous recovery. Eventually he was forced to switch me to T4 and the symptoms returned yet again and remained until I started self medicating with t3.

I probably should have noticed the pattern but it's quite difficult when you're not even sure what is real and what isn't. The doctors should certainly have noticed!

I'm feeling normal again and it is great to have my brain back and I'm even considering training as a teacher on the School Direct programme.

I have gone from being a scientist to "frankly insane" to possibly a teacher. I could have done without the bit in the middle though

Carolyn x

[PR4NOW in reply to PinkNinja]

CarolynB, I'm still thinking you need to go for that PhD in Biochemistry or Cellular Biology where you could apply the insight you have gained. You are one of the lucky ones, you managed to get your life back. It makes one wonder how many others could have their lives returned to them if they could only find adequate treatment. Regarding the Kelly T. study, another piece I read talked about the fact that they were using what are considered 'supraphysiological' doses, i.e. doses that suppressed the TSH. They were hesitant to do this but received moral support from some of their colleagues so they proceeded and got good results. Doctors do not receive adequate training on T3, but then, the science is not adequate either. PR

[PinkNinja in reply to PR4NOW]

I would love to do such a PhD but I would need to win the lottery first I need to be working at the moment. The teacher training course is paid. It's considerably more than a grant would be. When I did my post grad research (before I went insane ) the grants were pitiful. I would enjoy it though

Carolyn x

[PR4NOW in reply to PinkNinja]

CarolynB, there is another fun area you might enjoy. I've been spending some time on methylation the last few weeks, it is another very promising but complicated area. mthfr.net/ dramyyasko.com/

Dr. Mullen works with Dr. Yasko and has a nifty little eBook you can download. nancymullanmd.com/

Methylation is probably involved in the various problems of the mind. PS We always need more good teachers. PR

[PinkNinja in reply to PR4NOW]

Thanks for the links. This is something else I am interested i but haven't got round to reading about. I shall have a read tomorrow when my mind is a little fresher

Carolyn x

[helvella in reply to PinkNinja]

I don't need a fresher mind. I need a brand new one!

[PR4NOW in reply to diogenes]

Diogenes, if you took a sample of USP desiccated thyroid powder and ran it through gas chromatography would you not be able to see the amounts of T4, T3, T2, T1, and Calcitonin? If there was any RT3 or thyronamines would they show up? Does it look at complete molecules only? Can it identify the parts of molecules or would you have to chemically break the molecules apart before the constituent parts can be identified? I'm also wondering how you would identify iodine or if it would unless it were pure iodine, not part of T4. PR

[diogenes Remembering in reply to PR4NOW]

It all depends on whether the molecules are stable to up to 250C. There are potentially up to 27 different thyronine related molecules. NDT will contain quite a lot of these, some in miniscule concentration. You have to get a unique signature from any given molecule, and if it breaks down, the problem is that the breakdown products may be mimicked by another molecule similar to it. With the potentially large number of molecules to separate, in NDT, the study would be very sophisticated, and GC might not be enough to do the whole job. Mass Spectrometry combined with GC or liquid chromatography would go further along the road. In this case unique fragments would be the vehicle for detection. Regarding iodide detection alone, this is at present described in the new USP for NDT control, so as to distinguish T4/3 content from iodine itself. From proteins like calcitonin, probably electrochromatography would be needed But rather I would go in for immunoassay as a detection method. This is designable as calcitonin-specific.

[PR4NOW in reply to diogenes]

Diogenes, I have never been able to find a sophisticated study where they actually did a thorough analysis of everything that is in NDT. Is that because there just isn't any real interest? Or because of lack of funding? Or both? PR

[diogenes Remembering in reply to PR4NOW]

I suspect that when T4 monotherapy came in, there was no interest or funding to follow up.

[PR4NOW in reply to helvella]

Rod, I would like to see a study where they do a full analysis of what is in NDT at what amounts but I have never seen one, have you? You would think that someone must have done that. PR

[helvella in reply to PR4NOW]

I am quite certain that RLC, Erfa, Forest, etc. have done such analyses.

I have an email somewhere - but cannot find it at the moment - from Erfa or RLC saying something about this - but not in sufficient detail to be of any real interest.

[PinkNinja in reply to helvella]

There are different isomers of t2. I wonder if the t2 isomer produced is dependent on whether it was converted from T3 or rT3...

I see a Google search in my future

Carolyn x

[PR4NOW in reply to PinkNinja]

Is that a structural or stereoisomerism? Can only odd numbers be an inner or outer ring situation like T3 and RT3? PR

[PinkNinja in reply to PR4NOW]

My biochemistry is extremely rusty but there is 3,5-t2, 3'5'-t2 and 3,3'-t2 as far as I can find out. Are the first two stereo isomers and the third structural? I think I need to brush up a bit.

[PinkNinja in reply to PinkNinja]

Scratch that. They're all structural. It took me a while to remember the nomenclature.

[helvella in reply to PinkNinja]

You don't need to work it out these days!

Go here:

pubchem.ncbi.nlm.nih.gov/

Type in "diiodothyronine" and Go...

Beware - that lists all sorts of things but it is quite amazing.

[PinkNinja in reply to helvella]

Brilliant! That is very cool It also confirms what I remembered... eventually.

Biochemist was more of a hobby for me. Although I was actually reading physics, my room mate was a pharmacy student so I used to borrow her books when I was bored of mine (some of which were extremely dry reads).

I can see me spending time on Pub chem

[PR4NOW in reply to helvella]

Rod, Oh Goodness, there goes at least another week lost. Nifty link Rod, which I'd been smart enough to find that years ago. PR

[Coastwalker]

Agree with sandi above, no wonder the naive mice reduced immobility with the tail suspension test, poor things couldn't run anywhere, no wonder they were depressed.

Thanks for spotting and passing on this new info Helvella, the puzzle will all come together one day and make sense.

[PinkNinja]

Very interesting! I need to have a proper read, preferably with Google to hand

Thanks for posting

Carolyn x

[Doctor_Who]

Yet again the mantra and religion of the NHS and mainstream western endocrinologist has been proven to be false. These doctors proclaim absolutely that TSH (+/- freeT4) are the only tests that are required to accurately diagnose 100% of thyroid problems. This is not based on evidence based medicine (EBM) as these conclusions were presumed and established, or "written in stone", long before the doctrine of EBM was established in medicine. These presumptions and conclusions are unassailable because it has been established that if you give a healthy person extra/ too much thyroxine, they may develop heart or bone problems. Therefore, to run the studies or experiments to investigate once and for all whether the TSH assay (+ freeT4) can diagnose all thyroid disease would be heresy. To run the studies or experiments to determine whether the TSH assay can reflect and guide the required dose of T4 cannot be done as, according to doctrine, this would mean treating some of the subjects, some of the time, with "too much" T4, thereby causing or risking harm. Another of these doctrinal commandments, written in stone, is that T2 and T1 are the inactive metabolites of T3 ( which is the 10x more potent metabolite of T4 ). This paper now proves that T2 is an important controller of mitochondrial metabolic function (as T4 and T3 are), at least in the neurological tissue studied that is responsible for mood, psychomotor activity, diurnal rhythms and general neurotransmitter and neuron generated hormones.

This is progress, but the TSH extreme fundamentalists (most endocrinologists) will probably have to die before accepting anything that contradicts their religious doctrine.