GAD inhibition (eg; ethanolamine-o-sulfate)- any human data

[fatchains]

GAT inhibition (eg; ethanolamine-o-sulfate)- any human data

Im curious about the effects of inhibiting GABA degradation in human.
I came across a curious molecule, ethanolamine-o-sulfate, which in rodents seems to be a sedative, anticonvulsant, or anything else that one would associate with higher levels of GABA. [BTW, ethanolamine alone is a class of antihistamines we know of, like OTC sleep aids and allergy meds.] But the sulfate ester, is a GABA transaminase inhibitor (increasing GABA levels) . I have the rodent literature on ethanolamine-o-sulfate, but Im curious what happened to the human data- is there any or if not why not- why wasn't it looked at more closely?

Anyone know?

Any info on other GAT inhibitors in human (besides valoproic acid and vigabatrin; which also hit GAT when they're NOT acting on other proteins)? Theres also cycloserine but its complicated- there may be a dosse where its reasonably selective for GAT but since its a main treatment for TB much of the human data is using doses meant to inhibit cell wall production to treat TB. If anyone knows of cycloserine studies or data in human where smaller doses are used, that would be interesting too.

 

[Limpet_Chicken]

Have taken reasonably high dose lemon balm decoction (Melissa officianalis, as much finely chopped balm as will fit in a liter glass jug, then filled with not boiling but very hot water, left to steep and consumed whilst still hot. Its very tasty actually, love the stuff. Seem to have less frequent seizures whilst drinking it, and its calming if something has left the faeces distributed over a wide, if localized area courtesy of the air distribution equipment.

You know? the sort of sudden unforseen event that just leaves you shitting feathers that you just spat and sucked back on in again in sheer fury, frustration and generally fixing for a target with eyes, just so there is something to grab, swear at profusely and tear the fuck out. It helps bring one back to a state wherein one is less likely to eat somebody.

 

[sekio]

It helps bring one back to a state wherein one is less likely to eat somebody.

Thats an, uh, novel way of describing the effects of lemon balm.

But chalk another vote up for that stuff; not only is lemon balm a tasty & terpene-laden herb to make into tea (repels mosquitos as well) and a proven sedative (check PubMed), I understand it is fairly cosmopolitan and is pretty much a weed in many parts of the world.

The reason you don't see ethanolamine-O-sulfate used is probably because it will be rapidly degraded in the blood and GI tract to ethanolamine &c. - the cited studies I saw on Wikipedia involved injection directly into the brain cavity (intracerebroventrical administration), which is something that you can do with mice repeatably, but not really with people.

As far as I know there are not a whole lot of compounds that act selectively on GAT right now.

 

[bingey]

Man i wish i could inject IB....

 

[sekio]

I think most people would probably lack the sterile theater and proper technique for doing so without damaging the delicate matter in the brain. Also, you'd probably need to trepan yourself first - as gruesome as it sounds I'm pretty sure you can get a needle to penetrate a mouse/rat's cranium, but not so in humans.

"Cotton fever" or other hallmarks of poor injection hygiene, needle reuse, missing the mark with the needle, and the like, are partially excusable and usually survivable mistakes in IV drug usage. In ICV injections the same "accidents" would be likely crippling or fatal - meningitis, encephalitis, direct damage to the cerebral cortex, the possibility for all sorts of crazy interactions not normally seen (e.g. sugars like mannitol can cause changes in cerebral pressure when delivered directly to the brain) would all be far more common. The injection of any sort of particulate or plant matter might cause a full-fledged inflammatory response leading to eventual brain death, too. So you'd need to have a supply of really clean, sterile drugs and likewise a bunch of clean injection supplies. And plenty of topical povidone-iodine or other topical disinfectant... surgical gloves, surgical drape, and probably an assistant watching...


It ain't a thing to aspire to... is IV usage really too pedestrian for ya? (I think it's scary enough when people inject into weird places like their penis, forehead, or jugular due to a lack of other veins!)

 

[fatchains]

Thanks Seiko, that makes sense.

Still this compound made me wonder about something, though I didnt mention it as its tangentially related to my initial curiosity of tinkering with GAT.

How one could the increase production of Succinic Semialdehyde (SS) to enhance γ-Hydroxybutyric acid (GHB) production. Messing with GAT may be to risky; increasing SS production directly may produce a dangerous Glutamte inbalance since both are a product of GABA degradaton. Immediate or delayed health issues could arise if one messed with the Gluamate cycle. Either reducing Glutamate initially could really enhance overall inhibition (through increased inhibition and reduced excitation) or the rebound of excess Glutamate (which would likely occur as homeostatic metabolic processes are engaged) leading to potential seizogenic issues. So maybe GAT is the wrong approach.

BUT I wonder if there are drugs that bias the path SS takes by increasing the SS reductase activity or reducing SS dehydrogenase activity. Obviously there could be issues too, SS is important for all cells to produce a variety of important compounds, notably in a cells energy production machinery, but could a slight bias towards enhanced SS reducase activity (and thus more GHB) be a safer way to use GHB?

GHB is really neat but its therapeutic index makes is exceedingly dangerous (1g = fun, 2g = danger, 3g = possible/likely fatal). Since its produced endogenously, why not utilize the mechanisms already in place? Perhaps letting the cells do the work, knowing all the homeostatic processes and redundancies in cells, could recruiting endogenous GHB production be safer?

Im not really an expert on toxicology or cellular energetics, but do know neuropharm well enough to appreciate the potential of GHB as both a medicinal tool and recreational compound. Unfortunately, GHB ingestion directly is not safe for most people, particularly recreational use.

Sorry for the long text, just thinking out loud.

 

[fatchains]

Also, dont fucking get a hole in your head to inject drugs. Damn, why do you think the Blood Brain Barrier is so picky about what it lets through? Brain infections usually, and in the mice I work with, virtually always, lead to irreversible brain damage. When that damage approaches the midbrain, even nears the brainstem, c`est la vie.

We have chemists to help us get drugs to our brain- we dont need neurosurgeons for that.

Im almost scared to ask if that was even a serious suggestion because its not the first time someone asked about getting a catheter behind their ear or above their brow.

 

[bingey]

So you want to hook my brain
Sekio thank you for your penis... I mean input I injected into my penis once for kicks....

 

[fatchains]

Giving i.p. a whole new definition huh?

 

[Limpet_Chicken]

Increasing GHB receptor activity alone, without GABAb agonism to decrease glutamate levels is likely a bad thing, IMO. GHBr agonists are glutamate secretagogues, which is to a degree counterbalanced in the case of GHB itself, although it still has neurotoxic potential. But selective GHBr agonists, and likewise low levels of GHB, insufficient to activate (significantly) GABAb (the affinity for GHBr is orders of magnitude higher than for GABAb, at most, an incidental target, in a manner of speaking) are excitotoxic.

Tiagabine, and vigabatrin operate via GABA-transaminase inhibition, although vigabatrin certainly should be avoided like the plague, as its known to seriously fuck up eyesight in some cases, there quite a few variations on the tiagabine theme. In the case of vigabatrin, its reported that as many as 50% of users experience pathogenic visual field changes and color perception issues. There are reports that tiagabine also has been responsible for color perception changes according to wikipedia, although I've not looked further into it.

These are GABAc agonists, as well as well as transaminase inhibitors, and given that GABAc is highly expressed in the retina, and pathological changes involving GABAcRs are implicated in retinitis pigmentosa, it seems that it would make sense that this may be a broad spectrum effect due not to specific structures but to the increase in GABAc agonism, both via the direct stimulation through receptor binding of the drug, but also, potentially through increase in GABA levels/and/or increased persistence of GABA within the synapse.

Personally I need trepanning like I need a hole in the head.

 

[fatchains]

I tried to avoid GABAb-Rs, the dimerization of different subunits makes it really tough to define actual binding sites, not to mention typical proteoglycans and lipid rafts which complicate a lot receptor effects. I often oversimply GHB as a GABArho (now GABAc) receptor ligand and/or extrasynaptic GABAa-Rs (loosely defined post hoc by drug-binding to 2 types of subunits), at least preferential ligand at typical synaptic concentrations. But regardless, anything that similar enough to GABA, like GHB is, will bind to most GABA-Rs.
But for a moment, pretending the complexities of the postsynaptic effects of GHB are X, Id like to get some data on hijacking a neuron's enzymes to bias GABA degradation to GHB over other metabolites.
I did more reading on the known GAT inhibitors, and Im not convinced they're remotely "clean" enough to be selective. I know the saying in Neuropharm is a drug gets less specific 'over time,' but the GAT-I's Ive read about are so far from selective that those side effects could be from so many different targets. Albeit, you are right that GABArho or "GABAc" (its a GABA ion channel subunit which is not unique enough to be considered a third subtype, IMO) is found largely in the retina so those side effects make sense but I could also point to 5HT2A/C agonists (even newer, with greater selectivity than traditional ones), which have visual effects but not corresponding auditory ans somatosensory effects (proportional to visual effects) despite that 5th2a/c-Rs are found all through the cortex at certain layers.
Id need more info to be better informed about visual specific effects of GAT-inhibition. You may be right, definitely something to consider.
Any yeah, I need more GABAergics in general, like more dead space in my cortex. But a drug selectively increasing GHB production could push GHB made by Roche off SchIII, so theres no scheduling conflict, at least- just SchI. Plus GHB has a multitude of uniquely positive side effects at lower concentrations, like immuno-promotion (measured by a couple of indicators). Enzymatic GHB production could A) be legally sound, B) might be a self-limiting agent (eg, homeostatic mechanisms kick in to prevent over production or SS spillover to other enzymes) so abuse would be less appreciable.

Sometimes I wish I knew more chemistry and basic pharmacokinetics, but Id probably just be a smart guy in prison if I were.

Thanks for the input, wish there were more data.

 

[fatchains]

A great experiment would be to get an adenoviral vector to overexpress SS reductase or knock-down SS dehydrogenase and deliver it to limbic structures of marmosets (cheaper and easier to handle than macaques). Then some microdialysis to measure GABA/SS/GHB and a slew behavioral assays.