14 replies to this topic

[pi-]

I've noticed some academic experiments demonstrating that Sodium Valproate temporarily restores synaptic plasticity.

 

This is on account of it being an HDAC inhibitor.

 

However, if I look on the Wikipedia page http://en.wikipedia...._classification I notice that it is towards the bottom on the list:

 

HDI classification

 

The "classical" HDIs act exclusively on Class I and Class II HDACs by binding to the zinc-containing catalytic domain of the HDACs. These classical HDIs fall into several groupings, in order of decreasing potency:^[12]

1. hydroxamic acids (or hydroxamates), such as trichostatin A,
2. cyclic tetrapeptides (such as trapoxin B), and the depsipeptides,
3. benzamides,
4. electrophilic ketones, and
5. the aliphatic acid compounds such as phenylbutyrate and valproic acid.

 

i.e. The other items on that list I considered more potent HDAC inhibitors.

 

Might any of these other items be a better choice than valproate?

Edited by pi-, 09 July 2014 - 11:00 AM.

[pi-]

Also can anyone provide a clear explanation of exactly what an HDAC inhibitor does, and how it causes neural plasticity? The Wikipedia page is baffling to someone without technical training.

 

Note: I've googled a couple of those compounds from the above list, and some of them look lethal! Definitely not to be messed with! Take the first one for example; trichostatin A. The Wikipedia page makes it sound fairly benign, but contains a (footnote) link to a safety study. If you look at the safety study, trichostatin A comes out looking like a poison.

[renfr]

From what I understand, HDAC inhibitors prevent the deacetylation of lysine residues which is silencing the chromatin. Acetylation makes the chromatin active and active chromatin permits full gene expression.
I guess this can be useful if you have some kind of damage, you'd want to increase gene expression in order to fasten gene repair.

What I'm more scared of is someone thinking about using Valproic acid in order to inhibit HDAC.
If you look at the side effects and the action of this drug it looks like the perfect anti-nootropic.
It reminds me that it also causes brain damage in newborns whom mothers took the drug during pregnancy, I wouldn't touch that with a bargepole.

There's another drug that inhibits HDAC and is safe, it's some kind of sports supplement, it's called sodium something. I think Lostfalco mentioned it in one of his topics.

[renfr]

The drug is sodium butyrate.

Epigenetic enhancement--Sodium Butyrate, Trichostatin A, SAHA
Comments--Sodium butyrate has been excellent for me so far. Epigenetics is about to change the world so please get on board if you are not already. It involves changing in gene 'expression' without changing the underlying DNA and is ridiculously easy to do compared to gene splicing, etc. You can also increase your body's natural sodium butyrate production by eating fiber. The fiber causes your gut bacteria to release sodium butyrate with is an HDAC2 inhibitor which has been shown to massively increase learning and intelligence (mostly in rodents so far though). Check out the work of the Picower Institute http://picower.mit.edu/ for more. NaB does have other effects besides impacting brain function so be careful.

[Climactic]

Don't forget methionine which is a must-have for epigenetic effects. You don't want too much of it either, just a safe healthy amount.

[pi-]

@renfr, that quote also mentions Trichostatin A, http://en.wikipedia..../Trichostatin_A

 

that page links to http://www.fermentek...atin_A-MSDS.htm which is very scary, and makes it out to be poison by the looks of it.

 

What's going on?

[renfr]

@renfr, that quote also mentions Trichostatin A, http://en.wikipedia..../Trichostatin_A

 

that page links to http://www.fermentek...atin_A-MSDS.htm which is very scary, and makes it out to be poison by the looks of it.

 

What's going on?

That's a typical MSDS, it's just a template used for any kind of drug.

 

Look at the MSDS of thiamine (vitamin B1) : http://www.sciencela...?msdsId=9925232

 

Seems like a very dangerous substance too

 

But TSA still remains a research chemical so be cautious in any case.

[pi-]

renfr is quoting from this thread here: http://www.longecity...ic-experiments/

 

Thought I would link it in as it is a brilliant read (thanks renfr).

 

NOTE: I noticed my original post has been marked as dangerous/irresponsible, and as I learn more, it seems that this is indeed potentially a very dangerous area. I'm not going to try any experiment until I feel I have a reasonably good understanding of the whole situation, which may take weeks or months (and I may not even reach that point).  I think it is responsible behaviour to investigate and discuss the risks and dangers of messing with HDACi!

Edited by pi-, 09 July 2014 - 09:58 PM.

[medicineman]

From what I understand, HDAC inhibitors prevent the deacetylation of lysine residues which is silencing the chromatin. Acetylation makes the chromatin active and active chromatin permits full gene expression.
I guess this can be useful if you have some kind of damage, you'd want to increase gene expression in order to fasten gene repair.

What I'm more scared of is someone thinking about using Valproic acid in order to inhibit HDAC.
If you look at the side effects and the action of this drug it looks like the perfect anti-nootropic.
It reminds me that it also causes brain damage in newborns whom mothers took the drug during pregnancy, I wouldn't touch that with a bargepole.

There's another drug that inhibits HDAC and is safe, it's some kind of sports supplement, it's called sodium something. I think Lostfalco mentioned it in one of his topics.

Just because a drug is a teratogen, does not mean it is dangerous to adults. Some antibiotics are a testimony to that.

Have you read the pamphlet on aspirin, or any other drug? Side effect profiles are based on millions of people taking the drug and reporting them in phase three schemes (yellow card, etc) so if you were to administer placebo to millions of people, you'd get a list of side effects too.

Valproate, unlike many supplements and drugs taken by people on this forum and worldwide, is well studied. Years and years of study on the drug has concluded that not only is it an effective anti-epileptic (the most effective bar phenytoin and barbs), it is a great mood stabilizer. It promotes neurogenesis independent of its hdac inhibitory effects, and is neuroprotective in animal models of stroke. It is also safe, by a large margin. Large doses are needed to create unwanted effects that you mention, but what about low doses? I have taken low dose valproate, with the firm belief that it is helping me in a myriad of ways. I have regularly checked levels, which were always well subtherapeutic (and probably negligibly interactive with hdac from serum studies) and I am glad I gave it a try. Now, am I advising you to do the same? of course not. some of the stuff I am taking may seem too far, but I have specific targets in mind which I am trying to tackle (eg fluvoxamine for sigma1, low dose lithium and valproate for long term neurogenic/neuroreparative goals, low dose arbs to ameliorate some of the damage at-2 exerts on the body, low dose metformin, etc and much more that would make your jaw drop)

Knee-jerk reflexes are most likely scaring people from trying things which may have the potential to greatly enhance their lives. But I guess they also keep you Alive. Be informed then choose, and I lean on enhancement knowing the price I might pay.

[StevesPetRat]

You can eat a tablespoon of potato starch or plantain flour with every meal and ferment your own butyrate

[pi-]

So now Trichostatin A has my attention. It is #1 on Wikipedia's list, and Valproate is at #5.

 

Following renfr's link, I notice LostFalco has a category labelled Epigenetic enhancement -- Sodium Butyrate, Trichostatin A, SAHA

 

Digging into the thread, sodium butyrate gets eroded (apparently it has a half life of only six minutes, and is a weak HDACi to boot), as does SAHA (on grounds of being dangerous).

 

But might Trichostatin A be a possible candidate?

 

Also, can HDACi-s be classified under neuro-genesis / synapto-genesis? All of the explanations for HDACi I have seen are still in terms of entities I'm unfamiliar with, and I haven't yet done the necessary research, so I can't quite see the big picture. 

 

Apparently HDACi-s promote plasticity, but what does this actually mean? 

 

Does it mean that existing axon/dendrite branches move around and attach to new locations?

Does it mean that new branches form?

Does it mean new synapses form on existing branches, a la dihexa?

Or does it just mean that synaptic connections already established via LTP get returned into a plastic state? (*)

 

(*) I've heard people talking about valproate as an anti-noot. If this is what is happening, then is this what they are referring to?  It is shaking loose previously solid 'knowledge', so to speak.

[pi-]

I have started a separate thread for Trichostatin A (TSA) at http://www.longecity...trichostatin-a/

[pi-]

I would still love to gain some understanding of how HDACi-s promote plasticity.

 

renfr has given a breakdown...

 

From what I understand, HDAC inhibitors prevent the deacetylation of lysine residues which is silencing the chromatin.

 

Acetylation makes the chromatin active and active chromatin permits full gene expression.

I guess this can be useful if you have some kind of damage, you'd want to increase gene expression in order to fasten gene repair.

 

...but I still can't jump the gap from where he leaves off.  What is "full gene expression" and how does that lead to plasticity?

[pi-]

I've started to dig into the underlying biology.

 

Rather than put my current understanding in a forum post (which will get locked after a couple of hours), I am writing it up on my wiki:

 

http://mathpad.wikidot.com/hdaci

 

Which I will continue to modify as my understanding develops.

 

I very much welcome any input; if anyone would like to modify the wiki page please contact me. If you can see me going wrong or missing out valuable info please do get in touch by PM, or on one of {##neuroscience #biology #reddit-nootropics} on https://webchat.freenode.net/

 

pi

Edited by pi-, 15 July 2014 - 09:16 PM.

[pi-]

http://www.hdacis.com/index.html

 

^ this website is dedicated to HDACi-s