Explanation of study.

[markosheehan]

hi

I was reading through these studies on GABAB2 receptors and I am confused.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4205182/

this study is about a girl who had deficient GABAB2 function. This is apparently leading to intellectual problems and seizures. I understand the seizure thing but I always thought a decrease in GABA receptor function leads to increased intellectual capabilities. For example mice with Knockout GABAA 1 and 5 are resistant to cognitive problems brought about by certain Benzos. So is this the other way around/inverse here? or am I just interpreting it wrong here?

this study is about also mutations in GABAB2 function

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5384423/

"Here, we report the discovery of a de novo heterozygous missense mutation in the GABRB2 gene that encodes the β2 subunit of the GABAA receptor. Our in vitro studies indicate that this mutation causes EME via disruption of GABAergic inhibition in the brain."

so the people from this case report had seizures due to altered GABAB 2 function like the girl in the first study. But when I relate this back to cognitive problems in the girl it makes no sense to me.

I only have very basic knowledge in this stuff so hopefully your answers can be dumbed down enough for me to understand.

 

[sekio]

It's important to remember that rodent/murine models sometimes don't correspond to human responses to the drug. Maybe this is one of those cases where mice can compensate for loss of some GABA-A receptor function better than humans?

Also, this does talk about the Beta-2 subunit, not alpha-1 or alpha-5. So a different population of receptors than you'd think.

 

[markosheehan]

yes different subunits, but all GABA receptors are inhibitory. Or at least all studies ever on GABA seems to always start off with that. Also nearly a lot of Gaba antagonists actually have a nootrophic factor to them in rats and humans. It is rare to see something saying the opposite in terms of GABAB2. Also of note is I am pretty sure it is the same story for GABAB3 receptors. That is people with messed up GABAB3 seem to have a lot neurosystem disorders that are not usually associated with non working GAba receptors. maybe more drugs should be designed that target these areas as a better alternative to existing anxiolytics.

Anyway I really made this post in the hope that some quinazolinone derivatives sedatives/anxiolytics which act as GABAB2 agonists or PAM ( can someone tell me the answer to this)
could be a better option than Benzos.? if they are doing the reverse of what the studies I quoted are saying right?

I am probably looking at this too simplistically.

 

[sekio]

GABAB2 is not a receptor on its own, it encodes the protein for the beta2 subunit of the GABA-A receptor, which is actually a pentamer (composed of 5 separate proteins that come together and act as one). The Wiki article has a pretty good explanation of the different subunits.

Here's a simplified illustration of an example GABA-_AR.

There are different configurations possible, look on the Wiki for a big list of them.

 

[Cotcha Yankinov]

this study is about a girl who had deficient GABAB2 function. This is apparently leading to intellectual problems and seizures. I understand the seizure thing but I always thought a decrease in GABA receptor function leads to increased intellectual capabilities

Proper GABA function plays a critical role in the developing brain, as an example the direction of "growth cones" and how neurons wire up and connect with each other.

Disrupted GABA function during a developmental stage is very different than antagonizing certain GABA-A receptors

As another example, proper GABA cell function helps contribute to neural oscillations which are very important for cognition, disruption of such neural oscillations is a problem in neurodegenerative disease such as Alzheimer's. Decreasing GABA may lead to a net increase in excitability, but an increase in excitability doesn't always lead to an increase in performance, see the Yerkes-Dodson law

CY

 

[markosheehan]

There are drugs though that produce there effects though GABAAB2 subunit. I know the first study was on the girl but the other study was about people of all ages I think and it was talking about the same mutation in function. maybe for GABAAB2" Disrupted GABA function during a developmental stage is very different than antagonizing certain GABA-A receptors " n in but I know for GABAA1,4,5 subunits the same effects are seen in humans for knockout GABA subunits and antagonizing.

why are there hardly no drugs out there affecting gaba for treatment of alzheimers then?

anyway what I really want to know is could a potential GABAAB2 subunit affecting drug be made that would potentially have less adverse than benzodiazepines going of the evidence of them studies? can I use this logic at all(it doesnt sound like I can from your response). Even if my logic is wrong is there any other evidence yous know of to suggest it could be a better target then GABAA 1,5 subunit affecting drugs like the Benzos out there?

 

[Coolwhip]

I believe there is a russian anti anxiety drug which acts on beta subunuit containing gaba receptors, starts with an L I think.

But you won't see any(except for very specific purposes, used acutely) gaba antagonist drugs outside of research use because its a quick path to excitotoxicity and seizures.

 

[markosheehan]

hey coolwhip do you have any more info on that russian drug? or where/how I might find out what it is?

 

[Coolwhip]

Etifoxine is what I was thinking of, name wouldn't come to me earlier, don't know where I get an L from.

 

[markosheehan]

thanks.

 

[Limpet_Chicken]

Loreclezole? always been one I have wanted to try.

 

[markosheehan]

ye, that is interesting. I see you talked about it a while ago in some other post. Why have you not tried it.

Also what about the potent valerian analogues? have you looked into them? researchers a while back screened aload of compounds and there was a potent one.

 

[Limpet_Chicken]

Now that IS interesting. There are a plethora of active (in various ways) compounds present in Valeriana officianalis, do you mean active as a GABAergic PAM for the loreclezole site? (which, I just read, might be, intriguingly, the binding site for propofol at GABAaRs, so it would make sense to be quite cautious with high-potency analogs of valerenic acid.

I'd love to see a displacement assay done at recombinant beta2/beta3 containing GABAa receptors expressed in a suitable cell line of radiolabelled valerenic acid and radiolabelled loreclezole by propofol.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4988470/

 

[markosheehan]

I was talking about about modulation of GABAa B2/3 subunits.

http://jpet.aspetjournals.org/content/357/3/580#sec-18



I was referring to this ^

VA amide seems the most potent. at the higher doses locomotor activity was reduced by a lot. There is also a potent VA ester. VA TET also looks potent.

someone should sample VA A so people can get a better idea of how it is.

 

[markosheehan]

would VA A has the same risks as propofol?

how come etifoxine does not have the same risks if it also affects B2/3 subunits?

 

[Limpet_Chicken]

Well I am not certain I am correct about the binding site of loreclezole/valerenic acid being that of propofol, but papers seem to hint it may be the case. I don't know much about etifoxine really, I'll have to do some reading. But one could perhaps draw an analogy between lethality in something affecting a common receptor type between say, morphine and carfentanyl (I know the two have a different binding mode, with fentanyl type drugs inducing a different receptor conformation after binding but still, as a general analogy). If one has something super potent compared to a less potent ligand then it'll be a lot more dangerous. Also propofol isn't just a GABAa ligand, IIRC it also has effects on the endocannabinoid system and some other, more insidious effects.

It appears, especially at high doses to be toxic to mitochondria, and there is a propofol infusion syndrome which leads to a lipidaemia, fat accumulation around and in the heart muscle, severe lactic acidosis, it also blocks cardiac beta-adrenoreceptors and some types of cardiac calcium channels, not sure if it blocks other Ca++ channels located elsewhere, and appears to play some role in altering, especially with longer duration higher dose use, but cases exist of propofol infusion syndrome even when the duration was as low as 3 hours or so, a brugada syndrome-like EKG pattern preceeds imminent death, and the syndrome also includes severe rhabdomyolysis, blocks sympathetic nerve activity, and also interferes with the carotid baroreceptor reflex, which further aggravates cardiac issues.

Its rare, but very, very lethal if not monitored for and caught instantly with aggressive response to correct the metabolic acidosis, and also activated charcoal haemoperfusion, risk is increased with use of vasopressor agents and glucocorticoids.


From an animal study, copy, paste, and do excuse my not reformatting the way the text appears, I'm tired, I'm just about to go to sleep for the day and to boot, I'm also just having a strong dose of nitrazepam kick in along with chlormethiazole, plus IM morphine and oxycodone, along with oral tizanidine. Either I post this now or its going to look like a cat decided to walk over the computer keyboard and to urinate in it and cause the circuitry of this laptop to end up shorted left right and center, along with making this post stink of stale cat piss and islam, all rolled up in a burger bun carved from a dead rat, cored of it's anal sphincter with a rusty potato peeler knife so as to afford said islam-contaminated rancid feline piss an asshole to crawl up and die.

Either this post falls into the forum, or I fall over

The clinical syndrome of PRIS has prompted
research in animal models. Eighteen healthy male
rabbits were sedated with propofol 2% or sevoflurane
and endotracheally intubated in a recently published
study. The initial propofol infusion rate was 20
mg
.
kg
-1
.
h
-1
and was adjusted to maintain a stan-
dard level of sedation up to 65.7?4.6 mg
.
kg
-1
.
h
-1
.
All animals sedated with propofol but no animal
sedated with sevoflurane died. Blood biochemical
analysis was performed in serial blood samples and
histologic examination at autopsy. Serum liver func-
tion indices, lipids, lactate and creatine kinase were
significantly increased in the propofol group.
Histologic examination revealed myocarditis, pul-
monary edema with interstitial pneumonia, hepati-
tis, steatosis, and focal liver necrosis, cholangitis,
gallbladder necrosis, acute tubular necrosis of the
kidneys, focal loss of the urinary bladder epitheli-
um, and rhabdomyolysis of skeletal muscles in the
rabbits anesthetized with propofol. The authors con-
cluded that propofol was able to induce a fatal syn-
drome similar to PRIS in rabbits.
47
However, the
animal model is limited by high doses of propofol
compared to human doses

 

[markosheehan]

hey is clomethiazole more functional relative to barbituates?

Like could you take it and still get stuff done without passing out and blacking out like barbituates?

I hope a lot of them things you listed do not apply to loreclezole/valerenic acid

 

[Limpet_Chicken]

The propofol infusion syndrome appears to be due to physical properties of propofol, lipid based carrier also interacts with its plasma levels, and it appears specifically to disrupt the mitochondrial electron transport chain.

Loreclezole I can't say, I've never taken it and I don't know of a single human report who has.

Valerian? you aren't going to drop dead easily from a valerian OD.

Chlormethiazole, yes definitely. I find it very clear headed. Barbiturates themselves aren't just GABAa agonists, but AMPA type glutamate receptor negative allosteric modulators. Inverted ampakines essentially plus GABA agonists.

Chlormethiazole is a barbiturate/picrotoxin site agonist, but unlike barbs it doesn't block AMPA receptors. Very clear headed and functional. I take it each and every day, several times a day. Plus my rescue resort remedy for breakthrough seizures, is more chlormethiazole. Rarely, very rarely, also nitrazepam, but usually chlormethiazole and it is crystal clear headed stuff, no filthy hangover. Hasn't caused me any physical dependency used at therapeutic dosages for years, I'd not change anticonvulsant for the world. Love the stuff. And excellent recreational effects if used thus.

Easy to make, although as long as one is very careful not to get the toxopyrimidine fraction of the bisulfite cleavage stage of synthesis, on vitamin B1 (thiamine), and also, not being a benzo, a barb, or a Z-drug, being both very different from other sedative-hypnotics/anticonvulsants, the only drug of its kind used medically, and being damnably old school, it hasn't got that big neon sign proclaiming 'EVIL! EVIL! CRIMINALIZE THIS PATIENT FOR ASKING!! EVIL EVIL SATANSATANSATANSATAN!' like the others do, docs aren't so shit scared of the stuff.