260 replies to this topic

[Jbac]

6g of butyrate is roughly equivalent in potency to 250mg of Vorinostat. The only feasible way to achieve that is via fermentation.

again with the potatoes? :/

[celebes]

Actually equivalent is the wrong term, those doses are both above the threshold I should say.

[noveltyaddict]

If I remember correctly, you need 400mg of vorinostat to get the same dosage they used in their fear extinction studys. That would mean you'd have to take... 16 of those butyrate capsules. Sounds a bit much at first, but that is "only" 2.5 times what is the recommended dosage for other health problems. Why should we need fermentation and potatoes?

 

Edited by noveltyaddict, 05 May 2014 - 11:50 AM.

[Phoenicis]

People's aversion to butyrate as a product of fiber (RS or FOS etc) fermentation is a little silly.  It's healthy and not very expensive,  so why not just add Na butyrate into the mix and combine the effects?

Edited by Phoenicis, 05 May 2014 - 01:05 PM.

[noveltyaddict]

 

Specifically, and similar to D-cycloserine (see above), rescuing fear extinction deficits via HDAC inhibition requires a significant reduction in fear during an extinction training session (i.e. a learning effect, see epigenetic priming in the ‘Safety aspects’ section below) before HDAC inhibitors (at least class I HDAC inhibitors) can be effective

(http://www.ncbi.nlm....les/PMC3961057/)

 

Correct me if I'm wrong, but this means it's hard to produce that effect with butyrate with its half-life of about 15 minutes in humans. It generally takes about 1-2 hours of exposure training before a "significant reduction in fear" occurs. So you either have to eat A LOT of butyrate to achieve classic fear extinction. Or it might still be useable to benefit from the increased neuroplasticity through altering existing memories by introducing new information in reconsolidation period.

[StevesPetRat]

 viral reactivation issue?
 

Yeah, methylation is how your body deactivates viral DNA in infected cells, if I understand correctly
http://www.methods.i...ion_review.html
Here's an in vivo mouse study. They use 1200 mg/kg and I'm not sure if the usual mouse/human conversion would apply. But if it did that wouldn't be so fat from the dose you guys are talking about.
http://www.ncbi.nlm....les/PMC1900314/
I have at least post viral muscle twitching and maybe both myocarditis and encephalitis, so the possibility of exacerbating things is a bit scary. Though I'm at the brink anyway so what does it matter?

But it sounds like one has to face the fear and then become unafraid during the treatment which if I could do I wouldn't really need the help...

Edited by StevesPetRat, 05 May 2014 - 06:26 PM.

[formergenius]

But it sounds like one has to face the fear and then become unafraid during the treatment which if I could do I wouldn't really need the help...

 

Perhaps with co-administration of a proper anxiolytic agent it might still be worth considering?

[celebes]

TrkB and NMDA agonism are both fear extinctive in themselves (along with CB1, Mu, GABAB, 5-HT1A and H2). HDAC inhibition's upregulation of both (in the absence of therapy) is the most likely explanation for its effects. A big part of the phenotype of trauma or anxiety is just the direct consequence of diminished BDNF and NMDA activity (along with CB1, Mu, GABAB, 5-HT1A and H2). You would expect anything that corrected any of that to take a big chunk out of fear conditioning, which demonstrably it does. I think the 'window' was a misconception, an artifact of the design. What we're really doing here is disinhibiting the biological basis of 'resilience', As with anything involving changing the brain, that takes time.

 

And another thing: How many situations is exposure therapy actually useful in? Sure it works for phobias but those are pretty much defined by being irrational. How does it work with rational fear? Combat veterans: attack people who can't fight back? Assault victims: be the one doing the beating? Child abuse: become dependent on people who are nice to you? Bullying? Infidelity? Failure? Loss? Now all of those things are actually practiced by the people in those groups. But in an hour or two? What's more, the fear extinction studies exposed the rats to a single stressful event. How many people here have had exactly one stressful experience?

[StevesPetRat]

 Perhaps with co-administration of a proper anxiolytic agent it might still be worth considering?

That was my proposal. It got shot down. I'm going with NSI-189 and dihexa first then maybe try something like this.

[AOLministrator]

The stuff arrived. Looks very silky white. Tested a little bit and it has no discernible taste or smell.

 

During meditation I occasionally get moments of bliss so I'm waiting for such a moment to try the rest. Perhaps more of it will stay afterwards. A stuffy nose is going to make it difficult to sniff it so I might have to put it under the tongue or encapsulate it.

 

So, what happened?

 

 

Threads like this scare me: Some guy with anxiety problems trying to undo traumatic memories by reversing his entire epigenome with some research chemical from some rat pilot study in one single dose ... I mean, I am not afraid for him but afraid because that is quite delusional where I come from. Even more delusional than to bluntly just assume it must be most likely either because of the thyroid or because of other neurotransmitter or hormonal imbalances... and from the looks of it there are dozens of threads like this now on this site. I never realized. 

Edited by Aolministrator, 06 May 2014 - 03:27 PM.

[neuroatypicow]

Aoladminstrator - so where do you 'come from'? what are your qualifications to say that Tree's methodology is flawed, especially when so many other sanctioned remedies fall way short of achieving these goals?

i'm not being snarky, if you have a better idea i'd love to hear it. if there's no direct mechanism for this process then tell us so and with details please. it's not 'delusional', it's borne out of desperation and a desire to get past debilitating traumas using experimental means. everything else has failed, and many of us really don't have much to lose. quality of life is at issue here, and that's why you see so many of these kinds of threads here.

facing a traumatic memory and re-experiencing the concomitant anxiety does nothing by itself. the fear conditioning has no reason to reverse itself without a substance capable of (for lack of a better term) softening up the hold the brain has on these memories.

and summoning the boogieman of 'research chemical' isn't terribly helpful, especially around here.

 

speaking for myself,

i'm the other participant in this experiment, i received the other half of the vorinostat buy.

 

i just moved this past weekend, and the previous month has been the source of extreme anxiety and lack of sense of stability. not the time you want to hold an encounter group where you revisit every past traumatic event. 'let's begin with how crappy you felt all during the move!'

so i'm waiting until after we've gotten stable in the new place. i'm sick too, and don't want to dose Vorinostat while my body is compromised. in a couple of weeks, after i have a physical and labs done, l'll take a look at how i feel.

 

what i'm trying to accomplish is to dismantle the triggers that link severe averse memories to the physical manifestations of anxiety. they're interfering with everyday function, and need to be reclassified by some novel process. if conventional methods were adequate for this, i'd have already experience relief, as i've tried many of them. but this stuff has become hard-coded, and nothing short of a chemical intervention will move them.

for the experiment,

i'll prepare a setting for safe dosing and CBT. warm bath, candles, scented oils. i'll dose the vorinostat, and then a fast-acting, low duration anxiolytic like Selank to prevent re-experiencing the stress reaction from each memory.

then my wife and i shall pathwork through every acute traumatic event which i feel informs my present anxiety scripts: re-experiencing them, and with wife's help, unpack, re-interpret, hopefully de-fang them. that's really what we're trying to accomplish here - the de-linking of the memories from their involuntary physical reactions. therapy alone isn't very effective, hypnotherapy sometimes helps, anxiolytics just control the symptoms but don't affect the scripts.

look,

it'll either help (a little? a lot?) or it won't.

if yes, GREAT!

if no,

i'll just be out a few $, i'll have had a nice spa night,and it'll be just another brief experiment in a list of therapies i'll be trying this year including group buy substances, neurofeedback, hypnotherapy, intense weight training, and (as more of a fallback option) may even give a conventional psychmed a try again. i'll have to washout the metabolites from the one-time use of an anti-cancer medication from my body, and that's the worst of it.

then it's back to the drawing board.

 

[tree]

 viral reactivation issue?

 

Certainly the body de-activates its own DNA replication system during infections to prevent the infected cell from spamming the rest of the body. But this should be switched back on afterwards. I'm not sure if there are methylated viruses floating around which could get re-activated, but there could be viral components in your genome which might get re-expressed. Keep in mind though, it takes more than one component to make a virus. And no safe amount of HDAC inhibitor is going to activate every gene in your body, just a bunch here and there.

 

 

Threads like this scare me: Some guy with anxiety problems trying to undo traumatic memories by reversing his entire epigenome with some research chemical from some rat pilot study in one single dose ... I mean, I am not afraid for him but afraid because that is quite delusional where I come from. Even more delusional than to bluntly just assume it must be most likely either because of the thyroid or because of other neurotransmitter or hormonal imbalances... and from the looks of it there are dozens of threads like this now on this site. I never realized. 

 

 

Heh, I know exactly what you mean. I've read threads on this site that scare me too. I think there are a few threads about people drinking aquarium cleaner in the hope that it will make them young again. And when someone complained that the dozens of chemicals he takes simultaneously is making him throw up, he got angry comments that 'we all do that it's normal'. It's really not guys. I know ageing sux but there are worse things, and many of the people on this very thread can tell you about them.

 

The important difference is that I'm not trying to fix what isn't broken. And thanks to my education I'm capable and willing to read the actual literature involved. I suspect I know what I'm doing better than most psychotherapists. Certainly the compounds I've taken so far have less (registered) side-effects than many prescription medications.

 

 

But it sounds like one has to face the fear and then become unafraid during the treatment which if I could do I wouldn't really need the help...

 

Well, I've been thinking about that. I know I said I was waiting for blissful meditation to accompany the vorinostat, but I realized my foggy mind forgot about something which I said earlier in this thread: the mice didn't receive psychotherapy.

 

They had a trauma, received the HDACi, and re-experienced the trauma. The mice must have felt some fear and stress. But instead of the memory becoming fortified (as it normally would) it was either erased OR had the emotional attachment erased. So we must conclude that fear attached to a memory is either a necessary element OR simply not detrimental for the procedure to work.

 

If exposing yourself to a fearful condition caused blind panic than it might be too much, perhaps the brain can't overwrite that. But from what the mice experiments have shown, some fear should not be a problem at all. Mice are simple creatures so there shouldn't have to be a complex trick involved. HDACi seem to create a state in which emotional prints/trauma's can be more easier shed, without giving it much thought. Perhaps it's best to simply be a bit calm (or as close to it as you can), empty your mind, casually start to confront yourself with a build in source of stress and wait what happens. I'll certainly try this next.

 

In fact, I've tried a very small dose of vorinostat already but I want to wait a few days more and try again. I'll post afterwards.

Edited by tree, 06 May 2014 - 06:15 PM.

[5ht2a]

 

They had a trauma, received the HDACi, and re-experienced the trauma. The mice must have felt some fear and stress. But instead of the memory becoming fortified (as it normally would) it was either erased OR had the emotional attachment erased. So we must conclude that fear attached to a memory is either a necessary element OR simply not detrimental for the procedure to work.

 

 

Why should the memory become normally fortified? If no aversive stimulus is followed by the reactivation of the fearful memory, if anything should happen, it's extinction of fear. There is plenty of research which shows that fear extinction only takes place if there is a learning process involved: The fear HAVE to go up at first until it comes down and habituation is reached. If you do exposure therapy with patients that are on benzos, it just doesn't work.

 

That is exactly what they describe in the quote mentioned earlier:

 

 

Specifically, and similar to D-cycloserine (see above), rescuing fear extinction deficits via HDAC inhibition requires a significant reduction in fear during an extinction training session (i.e. a learning effect, see epigenetic priming in the ‘Safety aspects’ section below) before HDAC inhibitors (at least class I HDAC inhibitors) can be effective

 

So being on an anxiolytic while testing the HDACi might very well ruin everything. I don't want to disencourage you, I just think it is safer to do the trial (especially because of the limited amount) in a way that makes sure nothing disrupts the process. Just do the following: Make a record which reactivates the fearful memory, take the HDACi and start listening to it over and over. Even if it is very hard at the beginning, habituation will take place - if it's not after 60 minutes, it will be for sure after 2-3 hours. At least, that would be the process that the research with HDACis backs up. Maybe it will work in some other way too (like talking about the trauma etc.) but if it doesn't work, we are not sure if it was the wrong procedure or if the HDACi-approach just isn't the holy grail we all hope for.

 

 

 

Edited by 5ht2a, 06 May 2014 - 07:34 PM.

[Phoenicis]

Out of academic interest - Can and should anything be done to attenuate this viral reactivation? Examples could be l-lysine, zinc, NAC, vitamin D antivirals like Valacyclovir? In fact - wouldnt reactivation be a strategically good time to attack the viruses? 

 

 

 viral reactivation issue?

 

Certainly the body de-activates its own DNA replication system during infections to prevent the infected cell from spamming the rest of the body. But this should be switched back on afterwards. I'm not sure if there are methylated viruses floating around which could get re-activated, but there could be viral components in your genome which might get re-expressed. Keep in mind though, it takes more than one component to make a virus. And no safe amount of HDAC inhibitor is going to activate every gene in your body, just a bunch here and there.

[...]

 

Edited by Phoenicis, 06 May 2014 - 07:50 PM.

[tree]

Why should the memory become normally fortified? If no aversive stimulus is followed by the reactivation of the fearful memory, if anything should happen, it's extinction of fear. 

 

Correct. I was thinking of a second shock but they didn't receive this, it was only a conditioned fear response.

[celebes]

 

 

 the memory... was either erased OR had the emotional attachment erased. 

 

 

 

I really don't think either of those things is happening.

[tree]

 

 

 

 the memory... was either erased OR had the emotional attachment erased. 

 

 

 

I really don't think either of those things is happening.

 

 

That IS the whole idea of memory attenuation. You alter the memory in one way or another. It's not like the mice have become fond of electric shocks, they just don't associate the cues with the shocks anymore.

[AOLministrator]

@Tree:

 

I am uninterested in reading the rest of the stuff in this thread, it is just too much irrational behavior mixed with amateur science.

 

 

 

But let me tell you this: what you seem to want to accomplish is plainly to just bust your current default mental state apart and start with something new. People have been doing magic mushrooms for that purpose for centuries... and I can personally recommend that over anything else to anyone capable of making informed decisions not susceptible to schizophrenic psychosis (including SSRIs or LSD). Eat a little bit of the stuff, get to know it. Then eat a mega dose and have an intense trip. If you did it right, you will feel mostly free of depression and anxiety or something, in any case magically different several weeks after until everything settles again to that which makes most sense to your cognitive mode of operation, hard to express that properly, but everything you feel and perceive happens for a reason (obviously) and if those reasons are solid, necessary or plainly the byproduct of biological realities you will revert to exactly that. And imho you aren't traumatized and your theory is most likely just BS. There could be anything going on in your body or your psyche, in the way you learned to perceive things, that no one understands or can understand yet and you are just misinterpreting stuff to make at least some sense of it. But you can't force things to make sense, if you don't know then you don't know.

 

I am not exactly sure why antidepressants even work, they just cause anxiety in me. But I suspect it is the same mechanism, they just break you out of it and force you to reevaluate what you perceive.

 

So if that is your goal and you are neither retarded nor nuts then do magic mushrooms. THAT makes a thousand times more sense than trying to reverse your epigenome a little bit ... you know the shit in your head is complicated and in the next 25 years no one will understand much of it in any meaningful manner. It is really important to admit that to ourselves, first of anything, or else we will just be fooling ourselves and suffer the consequences. Desperation move: do hallucinogens, preferably magic mushrooms they are the most friendly of them all. Non-desperation mode: not available yet.

 

I recently found this, the guy is biased towards environmentalism but other than that pretty entertaining: 

Edited by Aolministrator, 08 May 2014 - 07:08 AM.

[tree]

See what happens when you show someone the courtesy of humouring their viewpoint? They turn right around and verbally throw up in your face. That will teach me.

[neuroatypicow]

i for one am sure glad we have professor here to set us straight with the peer-reviewed, Darpa-sanctioned Magic Mushroom Method of PTSD treatment. that's far more rational than our ideas.

[neuralis]

Magic mushrooms can do wonders for psychological issues. Unfortunately they can do nothing for neuronal abnormalities..

[AOLministrator]

Magic mushrooms can do wonders for psychological issues. Unfortunately they can do nothing for neuronal abnormalities..

 

What neuronal abnormalities are you talking about though?

 

(Not responding to the other people here, just too much rage.)

Edited by Aolministrator, 09 May 2014 - 05:25 AM.

[neuralis]

Well I'm no expert in this field by any means, but to me it seems if persistent anxiety is hardcoded into your neural network it is not normal by any means. 

 

I've been suffering from deliberating anxiety for the bigger part of my life and there seems to be no permanent cure. Amongs other things I've tried I've had countless of experiences with mushrooms with no permanent success. So if there might be hope in improving the quality of my life through an experimental drug, I'm all for it!

[Phoenicis]

While I agree that no one should go running off taking any of these compounds without seeking independent medical advice from a doctor, I just want to bring something up for discussion purposes. 

 

What I want to discuss is butyrate and its prodrug tributyrin - people have noted how quickly butyrate is metabolised, but it seems tributyrin has much better pharmokinetics and the other interesting thing is that tributyrate is sold as a food grade flavor?!  10kg for 200 British pounds? Am I mistaken? Apparently it's naturally present in butter as well.

 

Tributyrin, a Stable and Rapidly Absorbed Prodrug of Butyric Acid, Enhances Antiproliferative Effects of Dihydroxycholecalciferol in Human Colon Cancer Cells

 

 Tanja Gaschott, Dieter Steinhilber*, Vladan Milovic, and Jürgen Stein2

 

"Butyrate, a normal constituent of the colonic luminal contents, is formed by bacterial fermentation of unabsorbed complex carbohydrates in the mammalian digestive tract. In normal colonic mucosa, butyrate serves as a primary energy source, promotes growth of normal colonic epithelial cells in vivo and in vitro and plays a role in preventing certain types of colitis (1). In contrast, in a wide variety of neoplastic cells, butyrate acts as a potent antineoplastic agent, i.e., it inhibits growth and induces differentiation, restoring normal phenotype and function (2). The studies done during the last decade provide multiple lines of evidence that butyrate indeed interferes with the pathogenesis of colorectal cancer. Butyrate inhibits DNA synthesis and arrests growth of neoplastic colonocytes in G1 (3), modifies expression of genes involved in chemotherapy resistance (4) and in cell proliferation/differentiation (5, ,6), and induces apoptosis by a p53-independent pathway (7). At least some of butyrate’s antineoplastic effects in colon cancer cells may be due to its synergistic action with another antiproliferative agent, 1,25-dihydroxyvitamin D3 [dihydroxycholecalciferol; (OH)2D3]. In various cancer cell lines it has been shown that butyrate and (OH)2D3 act synergistically in reducing proliferation and enhancing differentiation of neoplastic cells (8, 9, 10).

 

In spite of its early promise, butyrate is not among the drugs used for cancer treatment. The major problem has been to achieve and maintain its millimolar concentrations in blood. Butyrate is metabolized rapidly as soon as it enters the colonocyte via its active transport system (11, 12, 13), and its plasma concentrations are far below those required to exert its antiproliferative/differentiating actions.

 

A prodrug of natural butyrate, tributyrin, is a neutral short-chain fatty acid triglyceride that is likely to overcome the pharmacokinetic drawbacks of natural butyrate as a drug (14). Because it is rapidly absorbed and chemically stable in plasma, tributyrin diffuses through biological membranes and is metabolized by intracellular lipases, releasing therapeutically effective butyrate over time directly into the cell. Compared with butyrate, tributyrin has more favorable pharmacokinetics (14, 15, 16) and is well tolerated (17). Liquid tributyrin filled into gelatin capsules and administered orally resulted in millimolar concentrations of butyrate both in plasma and inside the cell (17). In vitro, tributyrin has potent antiproliferative, proapoptotic and differentiation-inducing effects in neoplastic cells (18, 19, 20). In this study, human colon cancer cells (Caco-2) were used to investigate the effects of tributyrin on growth and differentiation."

 

 

CLINICAL TRIALS -

 

1) Phase I study of the orally administered butyrate prodrug, tributyrin, in patients with solid tumors.

 

Butyrates have been studied as cancer differentiation agents in vitro and as a treatment for hemoglobinopathies. Tributyrin, a triglyceride with butyrate molecules esterified at the 1, 2, and 3 positions, induces differentiation and/or growth inhibition of a number of cell lines in vitro. When given p.o. to rodents, tributyrin produces substantial plasma butyrate concentrations. We treated 13 patients with escalating doses of tributyrin from 50 to 400 mg/kg/day. Doses were administered p.o. after an overnight fast, once daily for 3 weeks, followed by a 1-week rest. Intrapatient dose escalation occurred after two courses without toxicity greater than grade 2. The time course of butyrate in plasma was assessed on days 1 and 15 and after any dose escalation. Grade 3 toxicities consisted of nausea, vomiting, and myalgia. Grades 1 and 2 toxicities included diarrhea, headache, abdominal cramping, nausea, anemia, constipation, azotemia, lightheadedness, fatigue, rash, alopecia, odor, dysphoria, and clumsiness. There was no consistent increase in hemoglobin F with tributyrin treatment. Peak plasma butyrate concentrations occurred between 0.25 and 3 h after dose, increased with dose, and ranged from 0 to 0.45 mM. Peak concentrations did not increase in three patients who had dose escalation. Butyrate pharmacokinetics were not different on days 1 and 15. Because peak plasma concentrations near those effective in vitro (0.5-1 mM) were achieved, but butyrate disappeared from plasma by 5 h after dose, we are now pursuing dose escalation with dosing three times daily, beginning at a dose of 450 mg/kg/day.

 

2) Clinical and pharmacologic study of tributyrin: an oral butyrate prodrug

 

Martin J. Edelman, Kenneth Bauer, Shyam Khanwani, Nancy Tait, Jane Trepel, Judith Karp, Noble Nemieboka, Eun-Joo Chung, David Van Echo

 

Purpose

Butyrate is a small polar compound able to produce terminal differentiation and apoptosis in a variety of in vitro models at levels above 50–100 μM. Previously our group demonstrated that daily oral administration of the prodrug, tributyrin, is able to briefly achieve levels >100 μM. Given in vitro data that differentiating activity requires continuous butyrate exposure, the short t1/2 of the drug and a desire to mimic the effects of an intravenous infusion, we evaluated a three times daily schedule.

 

Patients and methods

Enrolled in this study were 20 patients with advanced solid tumors for whom no other therapy was available, had life expectancy greater than 12 weeks, and normal organ function. They were treated with tributyrin at doses from 150 to 200 mg/kg three times daily. Blood was sampled for pharmacokinetic analysis prior to dosing and at 15 and 30 min and 1, 1.5, 2, 2.5, 3, 3.5 and 4 h thereafter.

 

Results

The patients entered comprised 15 men and 5 women with a median age of 61 years (range 30–74 years). Prior therapy regimens included: chemotherapy (median two prior regimens, range none to five), radiation therapy (one), no prior therapy (one). There was no dose-limiting toxicity. Escalation was halted at the 200 mg/kg three times daily level due to the number of capsules required. A median butyrate concentration of 52 μM was obtained but there was considerable interpatient variability. No objective responses were seen. There were four patients with prolonged disease stabilization ranging from 3 to 23 months; median progression-free survival was 55 days. Two patients with chemotherapy-refractory non-small-cell lung cancer had survived for >1 year at the time of this report without evidence of progression.

 

Conclusion

Tributyrin is well tolerated and levels associated with in vitro activity are achieved with three times daily dosing.

 

3) No results posted here? http://www.clinicalt...ibutyrin&rank=1

 

 

[StevesPetRat]

I've been doing pretty well on a combo of cal/mag butyrate, high potency CBD oil, and 1.5 mg c60oo. My long term memory has been firing like nuts, though that might be due to some other stuff I'm going through.

[Phoenicis]

Given that we know that we can achieve therapeutically effective release of Na butyrate in vivo via tributyrin, I am curious as to what effects it can have on cognition and fear extinction. It's also cheap. I think it should be studied further. 

 

Another interesting thing I came across was the selective HDAC 3 inhibitor RGFP966. Here it was used to enhance the extinction of cocaine seekinng behavior: http://www.pnas.org/...364110.full.pdf

[5ht2a]

There we have a cheap and bioavailable HDACi! Very interesting find Phoenicis - thanks for sharing it.

Edited by 5ht2a, 15 May 2014 - 06:19 PM.

[LexLux]

Could someone point me to evidence that tributyrin is dangerous, I have yet find any? 

 

 The Potential of HDAC Inhibitors as Cognitive Enhancers Annual Review of Pharmacology and Toxicology

Vol. 53: 311-330 (Volume publication date January 2013

 

Histone acetylation is a prominent epigenetic modification of the central nervous system that is unequivocally associated with an increase in the rate of gene transcription. Because gene transcription, in turn, plays an important role in long-lasting forms of memory, histone acetylation generally favors long-term memory, whereas histone deacetylation impinges on it. Histone acetylation is also amenable to pharmacological interventions—predominantly by the use of histone deacetylase (HDAC) inhibitors—and has therefore spurred considerable interest as a putative target of cognitive enhancement. Because of the ubiquitous presence of histone acetylation, HDAC inhibitors have great potential not only to treat cognitive impairment resulting from neurodevelopmental and neurodegenerative disorders but also to serve as cognitive enhancers for the cognitively healthy. In this review, we summarize the state of the art of HDAC inhibitors as cognitive treatments or cognitive enhancers; describe a new model of their mode of action, epigenetic priming; and caution against their unsupervised usage, despite their overall great promise.

Edited by LexLux, 15 May 2014 - 06:19 PM.

[LexLux]

Side Effects:

With respect to translational implications for the use of HDACis as cognitive treatments or enhancers, the route of administration becomes a key issue. Researchers are pursuing systemic methods of administration, but such methods might trigger side effects in nontargeted organs. Two studies reported neurotoxic effects upon HDACi treatment in animal models (91, 92). Strikingly, because these treatments were administrations of NaB and TSA, the neurotoxic effects might be due to the inhibition of the neuroprotective HDAC1. To our knowledge, no other reports of side effects in animal models exist. Given the extensive use of HDACis as potential cancer treatments, some side effects have also been reported in humans. These are dose-dependent and include thrombocytopenia, fatigue, confusion, hepatotoxicity, and abnormal electrocardiograph effects (70). In general, however, HDACis are well tolerated (60), which is surprising given that systemic routes of administration preclude tissue or even cell-type specificity. This absence of drastic side effects in humans and animal models alike is even more surprising given the extensive cross talk of histone acetylation with other epigenetic modifications (93) and the resulting downstream consequences when only one epigenetic mark is affected. Because the brain performs a plethora of functions other than cognition, the notion of epigenetic cross talk is of particular importance in this organ. For instance, mood, anxiety, and depression also involve epigenetic modifications (35). In addition, chronically depressed patients as well as mice exposed to chronic social-defeat stress (a depression-like behavior-inducing paradigm in rodents) display reduced HDAC2 levels in the nucleus accumbens (94), a brain area involved in reward. Thus, reducing or inhibiting HDAC2 levels might not be desired in all brain areas. It would therefore be important to investigate histone acetylation (and other epigenetic modifications) in brain areas other than the ones involved in cognitive functions upon HDACi treatment aimed at memory enhancement. Doing so would help clarify whether a systemic administration results in systemic effects or only in effects in the targeted tissue. However, to our knowledge, such detailed studies are still lacking

 

[...]

 

CONCLUSIONS

 

In sum, HDACis have great potential as pharmacological treatments against neurological diseases characterized by memory impairments or as cognitive enhancers in the cognitively healthy. Their broad applicability and the remarkable absence of severe side effects strengthen this point. In contrast to the targeted therapeutic approaches aimed at enhancing cognition (111), HDACis represent a broader treatment at the level of chromatin, making it theoretically accessible to all genes implicated in learning and memory. Although alluring, such a nonspecific approach inherently harbors a greater potential for undesired side effects; therefore, any concerns about safety apply with even more vigor to HDACis. Nonetheless, HDACis might make it possible to reinstate some of brain cells’ natural chromatin plasticity that is lost during development or disease via epigenetic modifications

→ source (external link)

 

Source cited in that review for neurotoxicity:

 

Inhibition of histone deacetylation enhances the neurotoxicity induced by the c-terminal fragments of amyloid precursor protein

  

The AICD (APP intracellular Domain) and C31, caspase-cleaved C-terminal fragment of APP, have been found in Alzheimer's disease (AD) patients' brains and have been reported to induce apoptosis in neuronal cells. In recent, the C-terminal fragments of amyloid precursor protein (APP-CTs) have been reported to form a complex with Fe65 and the histone acetyltransferase Tip60 and are thought to be involved in gene transcription. In this study, based on the hypothesis that APP-CTs might exert neurotoxicity by inducing some gene transcription, we investigated the effects of APP-CTs on histone acetylation which indicates that transcription is actively going on and also on the relationship between histone acetylation and the cytotoxicity induced by APP-CTs in nerve growth factor (NGF)-differentiated PC12 cells and rat primary cortical neurons. Here we demonstrate that the expression of APP-CTs [C31, AICD (C59) and C99] induces increases in acetylation of histone 3 and histone 4 and that treatment with sodium butyrate, an inhibitor of histone deacetylase, significantly enhances the cytotoxicity induced by APP-CTs. The acetylation of histone plays an important role in allowing regulatory proteins to access DNA and is likely to be a major factor in the regulation of gene transcription. Taken together, our results suggest that APP-CTs exert neurotoxicity by transcription-dependent mechanisms and this might contribute to the pathogenesis of AD. © 2003 Wiley-Liss, Inc

 

 

A free review that covers side effects:

 

HDAC inhibitors and neurodegeneration: at the edge between protection and damage

The use of histone deacetylase inhibitors (HDACIs) as a therapeutic tool for neurodegenerative disorders has been examined with great interest in the last decade. The functional response to treatment with broad-spectrum inhibitors however, has been heterogeneous: protective in some cases and detrimental in others. In this review we discuss potential underlying causes for these apparently contradictory results. Because HDACs are part of repressive complexes, the functional outcome has been characteristically attributed to enhanced gene expression due to increased acetylation of lysine residues on nucleosomal histones. However, it is important to take into consideration that the up-regulation of diverse sets of genes (i.e. pro-apoptotic and anti-apoptotic) may orchestrate different responses in diverse cell types. An alternative possibility is that broad-spectrum pharmacological inhibition may target nuclear or cytosolic HDAC isoforms, with distinct non-histone substrates (i.e. transcription factors; cytoskeletal proteins). Thus, for any given neurological disorder, it is important to take into account the effect of HDACIs on neuronal, glial and inflammatory cells and define the relative contribution of distinct HDAC isoforms to the pathological process. This review article addresses how opposing effects on distinct cell types may profoundly influence the overall therapeutic potential of HDAC inhibitors when investigating treatments for neurodegenerative disorders.

 

 

Edited by LexLux, 15 May 2014 - 07:17 PM.

[5ht2a]

These are pretty massive doses they used in the studies... 30g is on the low side for a 75kg-man. But these are the doses required for an anti-cancer effect, I wonder how much is needed for fear extinction.

Edited by 5ht2a, 15 May 2014 - 08:11 PM.