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The root of depression? P11 Protein (S100A10) inducers and inhibitor list?

R

Roostr

Messages
11
Hi All,

I've been looking at some of the latest research around P11 (S100A10) protein and its mood effects.. It 's fascinating to me as a good candidate for a unified explanation of archetypal depression...

Brief overview of what we're talking about here: https://en.wikipedia.org/wiki/S100A10

-From my understanding the P11 protein binds to serotonin receptor proteins and effectively amplifies the neurotransmitter signals.
- Gamma Interferons (IFN-y ) and TNF-a increase P11 protein levels https://www.ncbi.nlm.nih.gov/pubmed/12645529
- NSAID's ibuprofen etc. block IFN-y and TNF-a, preventing up-regulation of P11 (explaining interaction with reduced SSRI effectiveness)
http://healthland.time.com/2011/04/25/how-advil-thwarts-the-effects-of-prozac/
- BDNF also increases expression of P11 protein, explaining Omega 3's, exercise effectiveness for lifting depression
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2929288/
-In major depression people have lower levels of P11 (prior to treatment with SSRi's MAOI's etc)
- SSRI's, MAOI's, and ECT all raise P11 levels eventually, generally coinciding with the symptoms lifting
- Ketamine up-regulates P11 protein, for a sustained duration, correlating with symptomatic relief
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4872431/
-Gene Therapy on the P11 S100A10 gene reverses depression in rodents.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3026098/
-Nobel prize winner Dr. Paul Greengaurd has a very interesting patent posted around using P11 for the next generation treatments of depression http://www.google.com/patents/EP2659913A2?cl=en , and a study here
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3933996/

I'm interested in (cautiously & scientifically!) hopping on-board for mood & energy improvements...


Can anybody suggest supplementary or dietary methods one might go about increasing expression of P11 (S100A10).. elevating Gamma Interferons (IFN-y ) and TNF-alpha levels?...and also avoiding its down-regulation.
Interestingly I previously had great results from NAC (n-acetylcysteine) which does also raise IFN-y and P11 https://www.ncbi.nlm.nih.gov/pubmed/12165081 ,
 
eljefe19

eljefe19

Senior Member
Messages
483
I don't know the answer to your question, but I take several supplements to boost th1 cyotkines, and depression is a well known side effect of IFN-gamma. I'm not depressed, but I am planning on trying Interferon Alpha and so I'm interested in how to prevent Interferon induced depression. Good luck on your search.
 
T

Tunguska

Senior Member
Messages
516
I don't usually target depression, but it is a nice side effect of anything increasing BDNF as you listed.

Targeting a single protein is probably only half effective. I follow another forum for years where someone released a "research chemical" 5-alpha-DHP which is the immediate precursor to allopregnanolone (bypassing the rate-limiting enzyme), which is also increased by a lot of antidepressants. I bought it to complement caffeine and lessen anxiety, but I found it provides the "cleanest" and "smoothest" antidepressant effect I've gotten. It's not dramatic nor very dopamine-heavy, it is a pure "huh everything seems alright" feeling while under stress (sorry I am bad at this). The effects of a single 15mg dose linger for 2 days (its safety is not proven, something about cancer but I bet not as bad as some antidepressants).

Long story short it convinced me allopregnanolone is a major player so unless p11 increases it significantly you'd be missing a stabilizing factor.
 
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T

Tunguska

Senior Member
Messages
516
failed to post any links there, to show you what I mean: http://journal.frontiersin.org/article/10.3389/fendo.2011.00117/full
Analyses to determine the optimal treatment regimen in the 3xTgAD mouse brain indicated that a treatment regimen of APα once per week was optimal for both inducing neurogenesis and reducing AD pathology. Pharmacokinetic analyses indicated that APα is rapidly increased in both plasma and brain following a single dose. APα is most efficacious when administered once per week which will contribute to its margin of safety
Click to expand...
A single weekly dose improves neurogenesis in AD so you can bet it has staying power to modulate depression and provide stability, which it also does. Everything is showing me BDNF/mTor + allopregnanolone combo really works for improving cognition and preventing degeneration, and is going to help depression the same, but combining this p11 + allopregnanolone I bet would give you interesting results just as well.
 
eljefe19

eljefe19

Senior Member
Messages
483
Tunguska said:
failed to post any links there, to show you what I mean: http://journal.frontiersin.org/article/10.3389/fendo.2011.00117/full

A single weekly dose improves neurogenesis in AD so you can bet it has staying power to modulate depression and provide stability, which it also does. Everything is showing me BDNF/mTor + allopregnanolone combo really works for improving cognition and preventing degeneration, and is going to help depression the same, but combining this p11 + allopregnanolone I bet would give you interesting results just as well.
Click to expand...

The drug Etifoxine creates an anxiolytic and analgesic effect through inducing alloprenelone, amongst other neurosteroids. Here and here.

What have you found in terms of how to best raise BDNF levels?
 
T

Tunguska

Senior Member
Messages
516
eljefe19 said:
The drug Etifoxine creates an anxiolytic and analgesic effect through inducing alloprenelone, amongst other neurosteroids. Here and here.

What have you found in terms of how to best raise BDNF levels?
Click to expand...

What I was already taking is good enough: tianeptine. Retroactively, it turns out I was doing almost all the right things, just not consistently/intelligently enough. I plan on going back on a form of it but more carefully. Also progesterone is good but I think it doesn't elevate allopregnanolone enough at least not in compromised people (due to rate-limiting enzyme and other reasons). So I plan on dosing more 5-alpha-DHP and less progesterone (with all the givens: high protein & amino acids, etc.). And other things less relevant to this thread. I mean basically this already worked. I can read whole scientific articles, after cessation of about a year of use of those. Stuff like NAC is useful but it never got me this far.

Looking at these (tianeptine is marketed as an anti-depressant first), the best solutions to depression might be indistinguishable from cognitive help.
 
R

Roostr

Messages
11
Valentijn said:
It might also be due to reducing amounts of glutamate. Cysteine, glutamate, and glycine combine to form glutathione, with cysteine usually being the one in shortest supply. So the NAC might be helping to mop up any excess glutamate, and creating something nice in the process.
Click to expand...


Do you know whether NAC suitable for longterm (lifetime) use, or is efficiacy or safey lost over time?
I wonder if non-acetyl 'L-Cysteine' would have the same effects on glutamate.

I do often see information inciting that Cysteine acts as an excitotoxin (Google Cysteine, excitoxin for examples).. although I have not fact checked this at all, and the internet is a minefield of misleading information and psuedo-science.
 
R

Roostr

Messages
11
Tunguska said:
I don't usually target depression, but it is a nice side effect of anything increasing BDNF as you listed.

Targeting a single protein is probably only half effective. I follow another forum for years where someone released a "research chemical" 5-alpha-DHP which is the immediate precursor to allopregnanolone (bypassing the rate-limiting enzyme), which is also increased by a lot of antidepressants. I bought it to complement caffeine and lessen anxiety, but I found it provides the "cleanest" and "smoothest" antidepressant effect I've gotten. It's not dramatic nor very dopamine-heavy, it is a pure "huh everything seems alright" feeling while under stress (sorry I am bad at this). The effects of a single 15mg dose linger for 2 days (its safety is not proven, something about cancer but I bet not as bad as some antidepressants).

Long story short it convinced me allopregnanolone is a major player so unless p11 increases it significantly you'd be missing a stabilizing factor.
Click to expand...

Thanks Tunguska, that's very interesting and I have some reading up to do! -- I think the best result is a lack of noticeable effect, just back to normal, feeling right, and not altered or high etc.. Having achieved the outcome you wanted have you investigated or found any ways to sustain this (and possible with diet & supps not drugs?)

*Edit*
Also (if you don't mind me asking) are you male or female? Would this have an effect on endogenous Progesterone levels.. e.g. differing outcomes for male and female?
 
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T

Tunguska

Senior Member
Messages
516
Roostr said:
Thanks Tunguska, that's very interesting and I have some reading up to do! -- I think the best result is a lack of noticeable effect, just back to normal, feeling right, and not altered or high etc.. Having achieved the outcome you wanted have you investigated or found any ways to sustain this (and possible with diet & supps not drugs?)

*Edit*
Also (if you don't mind me asking) are you male or female? Would this have an effect on endogenous Progesterone levels.. e.g. differing outcomes for male and female?
Click to expand...

I'm male and I took/take low-dose progesterone anyway. The low-dose doesn't have any real side effects, but if you had problems with androgens that might be different (or not!). It's a complex substance. But it may be a waste of time, I think allopregnanolone is more important and the rate-limiting enzyme will invariably be compromised in metabolic diseases (e.g. mTor inhibition + FoxO activation which is being discussed lowers the enzyme, such that opioids alone already enhance it).

I don't expect to be able to do this without drugs. My disease processes are still there and the drugs override them, to a degree that amino acids and friends just can't do. The best I hope for is to find more selective drugs that achieve the same effect. (I used to think differently but shit happens and your priorities change)

(though I can at least point out, that 5-alpha-DHP is endogenous, so it's about as natural as I think I'll find on that side)
 
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T

Tunguska

Senior Member
Messages
516
I accidentally landed on this abstract that summarizes I wrote, just to show you I'm not talking out of my ass:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3355888/
Abstract
The pharmacological action of selective serotonin reuptake inhibitor antidepressants may include a normalization of the decreased brain levels of the brain-derived neurotrophic factor (BDNF) and of neurosteroids such as the progesterone metabolite allopregnanolone, which are decreased in patients with depression and posttraumatic stress disorders (PTSD). The allopregnanolone and BDNF level decrease in PTSD and depressed patients is associated with behavioral symptom severity. Antidepressant treatment upregulates both allopregnanolone levels and the expression of BDNF in a manner that significantly correlates with improved symptomatology, which suggests that neurosteroid biosynthesis and BDNF expression may be interrelated. Preclinical studies using the socially isolated mouse as an animal model of behavioral deficits, which resemble some of the symptoms observed in PTSD patients, have shown that fluoxetine and derivatives improve anxiety-like behavior, fear responses and aggressive behavior by elevating the corticolimbic levels of allopregnanolone and BDNF mRNA expression. These actions appeared to be independent and more selective than the action of these drugs on serotonin reuptake inhibition. Hence, this review addresses the hypothesis that in PTSD or depressed patients, brain allopregnanolone levels, and BDNF expression upregulation may be mechanisms at least partially involved in the beneficial actions of antidepressants or other selective brain steroidogenic stimulant molecules.

Keywords: allopregnanolone, 5α-reductase type I, selective brain steroidogenic stimulants, GABAA receptors, BDNF, anxiety, aggressive behavior, PTSD
Click to expand...
You can definitely skip the SSRIs.
 
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