GABA A3/4/5, inflammation and mitochondria

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Ciprofloxacin
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GABA A3/4/5, inflammation and mitochondria

Unread post by Ciprofloxacin »

This post mostly related to cognitive part of PSSD.

I guess everyone already know that SSRIs increasing gaba levels.

https://www.ncbi.nlm.nih.gov/pubmed/14754790
" citalopram produced a mean increase of 35% in relative brain GABA concentration in the occipital cortex."
http://www.pssdforum.com/viewtopic.php? ... ist#p18961
"Recently I read about this forum about l-histidine that I tried.

It's the only thing that has worked for 10 years!
my erections have returned to 95% and maybe 98% when stack with cialis. My ejaculations came back very hard and my penis was bigger even at rest."

And also

"- cialis daily: very slight improvement in erection (maybe 75% of my pre-pssd)"
Both tadalafil and L-histidine decreases GABA level.


Now, I wondered which subunit is responsible for cognitive impairment, and looked up on some subunits.

https://epiphanyasd.blogspot.com/2017/1 ... 5-and.html

While reading, I remembered what my doctor said about my social phobia.
"Autism disorder have a wide chart and not all the time someone have to have all the symptoms."
I can't deny her sayings. I was a autistic from social aspect.
"Too many or too few the α5GABAA receptors or too much/little activity?

Regular readers will know that autism is all about extremes hypo/hyper, macro/micro etc. The same is true with α5GABAA, too few can cause autistic behaviors, but too many can impede learning. You need just the right amount.
The next variable is how well your α5GABAA are behaving, because even if you have an appropriate number of these receptors, you may not have optimal activity from them. Over activity from α5GABAA is likely to have the same effect as having too many of them.
Here it becomes very relevant to many with autism and inflammatory comorbidities, because systemic inflammation has been shown to activate α5GABAA. It has been shown that increased α5GABAA receptor activity contributes to inflammation-induced memory deficits and, by my extension, to inflammation-induced cognitive decline."
———————————————


https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4391624/
"these results show that α5GABAA receptor activity increases during inflammation and that this increase is critical for inflammation-induced memory deficits."

"Increasing α5GABAA activity I would see as possible strategy for people with high IQ, but some autistic features.
I think those with learning problems are likely to be the ones wanting less α5GABAA activity."
Apparently, increasing GABA levels really helped me. But I don't want to decrease my IQ for any reason. So I need to decrease a5.


————————


https://epiphanyasd.blogspot.com/2017/1 ... abra5.html

"In analyzing baseline disparities between the good and poor learners, Pahan's team found differences in two brain proteins. The gap was all but erased when cinnamon was given.


"Little is known about the changes that occur in the brains of poor learners," says Pahan. "We saw increases in GABRA5 and a decrease in CREB in the hippocampus of poor learners. Interestingly, these particular changes were reversed by one month of cinnamon treatment." "
https://www.ncbi.nlm.nih.gov/pubmed/27342118




SSRIs are generally increasing creb. But I find this:

https://www.ncbi.nlm.nih.gov/pubmed/16457782
"However, not all antidepressants increase CREB levels and/or activity, and reducing CREB levels in some brain regions also results in antidepressant-like behaviors"
Not have to be because of the creb when there are a3/5, but should be considered.



"The scientist readers of this blog may recall that there are two sub-units of the GABAA receptor that I am seeking to modify, to improve cognition. One is the α3 subunit and the other is the α5 subunit. Low dose clonazepam works for α3."
Alcohol withdrawal decrease a3:

http://www.pssdforum.com/viewtopic.php?f=20&t=1278
"According to wikipedia page on alcohol withdrawal something that cought my eye was downregulation of alpha1 and alpha3 subunits and upregulation of alpha4, aswell as nmda upregulation in particular affecting nmdar2b."
———————


NaB's other effect than gaba, is enhancing nmdar
"NaB is interesting because it is a d-amino acid oxidase inhibitor, which means that it will enhance NMDA function. So if you are one of those people with too little NDMA activity (NMDAR hypofunction) then sodium benzoate should make you feel better."
"NaB and Cinnamon
I am yet to determine how much NaB is produced by say 3g of cinnamon.
The clinical trials of NaB use 1g per day in adults. People using cinnamon, like Dr Pahan, for cognition or just lowing blood pressure and blood sugar use around 3g.
It is quite difficult to give a teaspoonful of cinnamon to a child, whereas NaB dissolves in water and does not taste so bad. "
I'll definitely try cinnamon if it doesn't worsen me further. If it does, it will be sign of inadaquate 5a reductase activity. Because it's a 5AR inhibitor like curcumin which worsened my symptoms.

But it also could because of GABA :D

I had used turmeric with 'black pepper' instead of curcumin. Piperine is a gaba activator. And another thing that worsening me is coffe. I became bit exhilirated after coffe, but I noticed it’s blocking emotions further. Though, I don’t have any emotion anymore after that turmeric-piperine mix trials.
The effects of caffeine, a naturally occurring stimulant, on the brain and plasma concentrations of neuroactive steroids were examined in the rat. A single intraperitoneal injection of caffeine induced dose- and time-dependent increases in the concentrations of pregnenolone, progesterone, and 3alpha-hydroxy-5alpha-pregnan-20-one (allopregnanolone) in the cerebral cortex. The increases were significant at a caffeine dose of 25 mg/kg and greatest (+188, +388, and +71%, respectively) at a dose of 100 mg/kg in rats killed 30 min after caffeine administration.
———————

Allopregnanolone is activator of GABA. And SSRIs increase allo production by increasing effectivity of 3a-hsd.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC23979/



"Our results indicate that the SSRIs fluoxetine, sertraline, and paroxetine decrease the Km of the conversion of 5α-dihydroprogesterone to allopregnanolone by human 3α-HSD type III 10- to 30-fold. Only sertraline inhibited the reverse oxidative reaction. SSRIs also affected conversions of androgens to 3α- and 3α, 17β-reduced or -oxidized androgens mediated by 3α-HSD type IIBrain."
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3031054/
"The progesterone metabolite allopregnanolone is a potent endogenous ligand of the γ-amino butyric acid –A (GABA-A) receptor"
Also
"There are physiological conditions in which allopregnanolone production increases acutely (e.g. stress) or chronically (e.g. menstrual cycle, pregnancy), thus exposing the GABA-A receptor to high and continuous allopregnanolone concentrations. In such conditions, tolerance to allopregnanolone may develop. We have shown that both acute and chronic tolerances can develop to the effects of allopregnanolone. Following the development of acute allopregnanolone tolerance, there is a decrease in the abundance of the GABA-A receptor α4 subunit and the expression of the α4 subunit mRNA in the ventral-posteriomedial nucleus of the thalamus."
Remember, Alcohol withdrawal increases a4 expression. SSRIs are increasing allopregnanolone permanently and cause tolerance.


————————

https://www.ncbi.nlm.nih.gov/pubmed/10899949
https://www.ncbi.nlm.nih.gov/pubmed/17454962
https://www.ncbi.nlm.nih.gov/pubmed/16019600

Social isolation (What I lived in my all life) decreases Allopregnanolone and gaba expression. The opposite of what ssri made.

————————

I don't sure about it but there is writing about how psychotic drugs damag
ing to mitochondria. And this is one of the comment on the epiphany blog (gaba a5)
"If mitochondria are dysfunctional or damaged, you will get an increase in inflammatory signaling which pertinent to this post can cause GABRA5 overexpression. Damaged mitochondria are passed from mother to offspring as paternal mitochondria are broken down and consumed immediately after fertilization of the egg."
https://www.ncbi.nlm.nih.gov/pubmed/21120605
" CLOM and NORF both reduced integrated mitochondrial function as shown by marked reductions in membrane potential (MMP) in mitochondria isolated from rat hearts. DMI also showed a similar but smaller effect, whereas, TIAN did not elicit any significant change in MMP. Moreover, micromolar concentrations of CLOM, DMI and NORF caused significant inhibitions of the activities of mitochondrial complexes (I, II/III and IV). The inhibitory effects on complex IV activity were most marked. TIAN inhibited only complex I activity at concentrations in excess of 20 μM. The observed inhibitory effects of antidepressants on the mitochondrial complexes were accompanied by a significant decrease in the mitochondrial state-3 respiration at concentrations above 10 μM. The results demonstrate that the apoptotic cell death observed in antidepressant-treated cells could be due to disruption of mitochondrial function resulting from multiple inhibition of mitochondrial enzyme complexes. The possibility that antimitochondrial actions of antidepressants could provide a potentially protective pre-conditioning effect is discussed."

In short:

SSRI ---> increased 3a-hsd ----> increased allopregnonolone -----> increased Gaba(a) a5 expression
SSRI --> I guess also elevate gaba levels generally?
SSRI ---> continuous elevation of allo ----> decrease of a4 subunit
caffeine ——> increases neurosteroids ———> worsen me further
Tadalafil and L-histidine ----> decreasing GABA -----> temporary improvement (He says %80-95)
Alcohol withdrawal ----> sensitizing a4 subunit ----> temporary improvement
Social isolation(what I used to be) -----> increases GABA(a) a5 subunit
Overexpression of a5 subunit ----> Cognitive impairment
Underexpression of a5 subunit -----> high IQ but autistic behaviours
SSRI ----> possible mitochondrial damage ---> Inflammation caused GABA(a) a5 overexpression ———-> cognitive impairment.

Trying Cinnamon Ceylon may be helpfull.
Last edited by Ciprofloxacin on Thu Sep 06, 2018 2:37 am, edited 3 times in total.
iull1k
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Re: GABA A3/4/5, inflammation and mitochondria

Unread post by iull1k »

Nice post, i will read it carefully when will have time. I quickly looked trough the lines and i'm happy that someone makes logical links not just "i think", "the cure is..."
Also one important thing is that me, and more guys had done brain MRI exam, no any inflammation was discovered, more then this, some guys reported shrinked parts of brain. I did not focus much on inflammation, maybe this kind of inflammation is at neuronal level, not at global tissue level, and can't be seen at any exam.
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Ciprofloxacin
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Re: GABA A3/4/5, inflammation and mitochondria

Unread post by Ciprofloxacin »

iull1k wrote:Nice post, i will read it carefully when will have time. I quickly looked trough the lines and i'm happy that someone makes logical links not just "i think", "the cure is..."
Also one important thing is that me, and more guys had done brain MRI exam, no any inflammation was discovered, more then this, some guys reported shrinked parts of brain. I did not focus much on inflammation, maybe this kind of inflammation is at neuronal level, not at global tissue level, and can't be seen at any exam.

Possibly. I done a MRI exam, wasn't there anyting either.

I could say, GABA much more responsible of pssd than we think. I want to add a few more things.

https://forum.propeciahelp.com/t/coffee ... azy/3703/5

This pfs guy not used to be drink coffee. You can read how caffeine reverse his all the symptoms. Think why? I had said in my post.

https://www.ncbi.nlm.nih.gov/pubmed/10837842

Allopregnanolone is decreasing in pfs and increasing in pssd. Caffeine should be help to pfs sufferers but does opposite for me (as it did).

I came a level that I can't read basic sentences even in my language. I don't think I could still continue to research. Maybe I could functional again if I can either inhibit 3a-hsd, reduce allo or decrease gaba generally. The worst part, the actual trouble will happen if I can't do this before 15 days.


I will post here some screenshots I took. Strongly advice to look them.
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Juvo
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Re: GABA A3/4/5, inflammation and mitochondria

Unread post by Juvo »

I think you are pointed in the right direction.

https://naturalsupremacy.com/2018/06/08 ... -lower-it/
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Ciprofloxacin
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Re: GABA A3/4/5, inflammation and mitochondria

Unread post by Ciprofloxacin »

It's very promising. It's like a list of PSSD symptoms. And literally I have all the symptoms in this list.

It's highly enough but one more thing to add:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2579978/

Primary insomnia reducing GABA levels.

http://www.pssdforum.com/viewtopic.php?f=10&t=1258

A bit me and others too getting some improvements from insomnia.


It wasn't 5HT1A desensitization. Presynaptic agonists work at sometimes, because they decreases gaba also.
The main reason of dopamine inhibition was not 2c.
Apparently, I think gaba is responsible for huge part of this disease.

So, I think we should look up to AKR1C1 C2 and C3 genes.

less 3a-hsd ---> less allo and 3a androstenadiol ----> normal gaba levels.

I'll post some of them SNPs in the genome topic.
iull1k
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Re: GABA A3/4/5, inflammation and mitochondria

Unread post by iull1k »

yes, i agree, it's the correct route. I had the same toughts for last 3 years. I will release an extensive file next weeks. I'm very busy with my work and i have no time for this now but i'm very happy that someone else got the same route. Coraggio had also the same theory.
Juvo
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Re: GABA A3/4/5, inflammation and mitochondria

Unread post by Juvo »

zadig777 wrote:benzos work directly on gaba and cause no sexual side effects
i dont get it how this can be the case rly
Biochemistry is complex. Why do some antidepressants that work on serotonin not cause PSSD? There's plenty of different actions/affinities for ligands on receptors. Just because sexual dysfunction is rarely reported from a benzo doesn't mean that a different drug with different actions and affinity relating to GABA doesn't cause our symptoms.

Personally Ativan is one of the few things to give me improvement. I think this is at the very least this research deserves more attention.
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Ciprofloxacin
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Re: GABA A3/4/5, inflammation and mitochondria

Unread post by Ciprofloxacin »

zadig777 wrote:benzos work directly on gaba and cause no sexual side effects
i dont get it how this can be the case rly
Ohkey, I can zimply telll you how this can be imposibblen’t

‘They have many binding sites on them. And, one can possibly change other one.’
Coraggio
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Re: GABA A3/4/5, inflammation and mitochondria

Unread post by Coraggio »

Glad to see talking and reaserching about gaba. Gaba plays a big role in our pathogenesis. We need to upregulate naturally
allopregnenolone and alpha4 gaba receptor subunit. Chronic SSRI downregulate both ( while acutely upregulate allpregnanolone biosynthesis).
iull1k
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Re: GABA A3/4/5, inflammation and mitochondria

Unread post by iull1k »

Coraggio wrote:Glad to see talking and reaserching about gaba. Gaba plays a big role in our pathogenesis. We need to upregulate naturally
allopregnenolone and alpha4 gaba receptor subunit. Chronic SSRI downregulate both ( while acutely upregulate allpregnanolone biosynthesis).
Hi Coraggio, can you check your PM? Thank you
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