from oldmustysad sent 13 hours ago
You mention in your article about HDAC inhibitors meant directly for memory, do you have any more information on those or links to more resources on classes of HDAC's and their associated proteins?
Question I got asked on Reddit and decided to write about it a bit and copy it here.
This is an interesting question when it comes to HDAC inhibition, or any type of drug for that matter, because there's selectivity for effect, selectivity for a specific HDAC protein, and selectivity for a body part like the brain. What they found with crebinostat, an HDAC inhibitor meant specifically for cognitive improvement, isn't necessarily a selectivity for a specific body part or effect, but a selectively to inhibit only the HDAC proteins implicated with memory. It inhibits mainly HDAC1, 2, 3, and 6, similarly to vorinostat, but with even more selectivity. It doesn't inhibit HDAC4, 5, 7, and 9 as much. If you want to learn more about what the different HDAC proteins do, I'd start by taking a look at these articles I posted,
https://www.dropbox....inI_zh5eUa?dl=0
which includes crebinostat's pioneering study. If you'd like to take a closer look at specific HDAC inhibitor effects or HDAC proteins, take a look at the studies in the HDAC discussion thread on Longecity, or go to PubMed, put in a search term like the one I've put in, HDAC6 memory, and sort by relevance. This is a quick and easy way to get into the literature.
Other than crebinostat and neurostat, the latter of which the structure is not even known publicly yet, there hasn't been much research done to find HDAC inhibitors that act solely on memory. This is because of the overlap in selectivity regarding specific effects, body parts, and HDAC proteins.
Enhancing selectivity for a specific HDAC protein, like HDAC3, isn't enough to narrow it down to only acting in the brain. The HDAC proteins that act on memory, addiction, fear, etcetera also act elsewhere in the body no matter what. These are mainly HDAC1, 2, 3, and 6. Even crebinostat would act elsewhere in the body at higher dosages. There has been a lot of talk and fear about the lack of selectivity for the brain, but before I wrote my HDAC article this was one of the things I looked into.
The way I see it is that by taking low dosages we are already increasing selectivity for the brain. We do the same thing with every other drug/nootropic we take for the brain... we take less cocaine, less Huperzine A, less phenibut, less coffee, less Alpha-GPC than we need to to have an appreciable effect anywhere else other than the brain. if we took too much, we'd have severely overblown effects in the brain, and side-effects would begin to appear in the body. Some of the researchers studying HDAC inhibition's cognitive effects mentioned the brain as being "primed for HDAC inhibitor use." This is because the mind is sensitive to the effect. The way HDAC inhibitors are used for cancer is they are prescribed in incredibly high dosages daily, which inhibit nearly 100% of HDAC, hold open the DNA on histones system-wide for a disordinate amount of time, as well as alter HAT/HDAC and other proteins' expression system-wide. A low-dosage, acute dose of an HDAC inhibitor does not inhibit 100% of HDAC, does not hold open histones, and will barely be noticed by our cells, including our brain's, but our *mind* will notice the change in cognition. This is because there only needs to be a small increase in the amount of transcription taking place for the desired effect to occur in our minds. In this way, we're increasing selectivity for our minds by taking lower dosages.
In regards to HDAC protein selectivity, the different HDAC proteins overlap in effect. You'll read one study saying HDAC3 in implicated in addiction, then another saying that HDAC2 and 11 are implicated in addiction, and in actuality both are true... HDAC1, 2, 3, possibly 6, 11, and possibly others are all implicated in addiction, as well as DNMT1, which controls methylation. HDAC1, 2, 3, 6, and 11 all have studies linking them to long-term memory, and several are implicated in fear extinction as well... I think that what is important right now is finding an HDAC inhibitor that sticks to inhibiting class I, IIb and IV HDACs, is safe, well-studied, and doesn't have any other effects other than HDAC inhibition. A couple other Longecity users found vorinostat a couple years ago that fits this bill, and after looking into it I fully agree with them.
In regards to selectivity of effect, it would be near-impossible, unless we began using weird, specific brain implants that secreted HDAC inhibitors, to separate HDAC inhibition's effects on memory, learning addiction, and fear, because these are all linked to similar mechanisms. HDAC1, 2, 3 and 6 are all implicated. HDAC 6 does stand apart, however, with effects on beta-amyloid plaque and tau fibrils. Crebinostat hasn't been studied nearly as much as vorinostat, and one problem they may find is that it is lacking in certain effects dealing with addiction and fear, as the relationships between HDAC8, 9, 10 and 11 haven't been fully researched. HDAC11 is at least partially implicated in addictive behaviors, so using a more pan-inhibitor like vorinostat may be more beneficial, or a compound somewhat in between crebinostat and vorinostat that also inhibits HDAC8 and 11 to a degree, for example. In a way, the way HDAC proteins are used in the brain already increases selectivity for certain mental processes, mainly the ones I've already described... learning, memory, fear and addiction.
