Selective translocator protein (TSPO) agonists

mitoMAN

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posted by @ljimbo423
Abstract

Benzodiazepines are psychoactive drugs and some of them also affect immune cells. We here characterized the inflammatory and infiltrating immune cells in the central nervous system (CNS) during the acute phase of experimental autoimmune encephalomyelitis (EAE) in animals treated with Diazepam.

Also, we evaluated the expression of Translocator Protein (18kDa) (TSPO), which is a biomarker of neuroinflammatory diseases.

The results indicate that Diazepam exerts protective effects on EAE development, decreasing the incidence of the disease and reducing the number of inflammatory cells in CNS, with a concomitant decrease of TSPO levels in brain tissue and CNS inflammatory CD11b+ cells.
https://pubmed.ncbi.nlm.nih.gov/28992974/


and

Conclusion: Diazepam through enhancement of activity of genes responsible for synthesis of corticosterone via its stimulatory action on Peripheral Benzodiazepine Receptors (PBRs) in adrenal glands and modulating activity of immune cells could be of high pharmacological interest as a potential anti-inflammatory agent.
https://clinical-epigenetics.imedpu...azepine-receptors-and-genes-for.php?aid=19469
 

MartinK

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This is very, very interesting!
Benzos really not my "favorite" group of drugs, but I had to start it because of insomnia, and it probably saved me quite a bit, and I get the impression that the small improvement I'm experiencing right now is because of benzo!
My PEMs are shorter, really shorter and sotf right now. (before - 6 days long, now - 2 days long)

How are you doing on some of these drugs? ;-)
 

Pyrrhus

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So far we tested two TSPO ligands both without long lasting improvements sadly.
There will be two other TSPO ligands in production, if those fail again then TSPO probably doesnt keep up to its promises.
Does your testing support the idea that ativan/lorazepam may exert its ME-alleviation action via the TSPO receptor, or is that still unclear?
 

leokitten

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Like most potentially promising things for ME which initially make sense wrt ME pathology (TSPO receptors on mitochondria affecting function, Ativan which has good TSPO binding causing short-term symptom relief in some), it will probably turn out to not be a long-term treatment solution. I really hope it would but I have doubts now.

For example, why can Ativan only be taken occasionally otherwise it stops working on ME symptoms?
 
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leokitten

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mitoMAN

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Does your testing support the idea that ativan/lorazepam may exert its ME-alleviation action via the TSPO receptor, or is that still unclear?
So far we tested two substances. EMAPUNIL (trialed for Anxiety disorders) up to 30mg with medium success. Studies went from 10-90mg tho and concluded that 90mg were needed. However this is out of our price class.

Then we tried PGL-36 a DA-1097 analogue and trialed 5-20mg. This helps lots of members for anxiety and ticks and has a very long half-life.
BUT it doesnt seem to work as magically on energy production as ATIVAN.

I have been taking 10mg PGL-36 every 4-5 days for 3 weeks now, it helps with anxiety, PGL-36 kind of removes anxiety in little things, which helps a lot in everyday life, like living in society, lol! It also reduces neural tics just as effectively as edaravone does or better (90% reduction).
This is very strange as PGL-36 has very HIGH affinity to TSPO and would be much more potent then just 1mg Ativan.

I am waiting on production of two more substances. Olesoxime (Studies took 500mg!!!) is a pure TSPO ligand and Cholesterol derivat. It was used for ALS and Neuropathies.

Then FGIN-1-27 which showed to slow down or reverse Autoimmunity.



My next experiment might be: Combining ATIVAN with a TSPO ligand. To still have the Gabba effect and maybe that potentiates the TSPO effect?
 

MartinK

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Just ordered etifoxine (Stresam) and will see what will do for me... looks like side effects are really minimal, I want to make a practical comparison of the effects with Alprazolam (Neurol) which I had to use for sleep, but probably brought more benefits.
 

Pyrrhus

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Then we tried PGL-36 a DA-1097 analogue and trialed 5-20mg. This helps lots of members for anxiety and ticks and has a very long half-life.
BUT it doesnt seem to work as magically on energy production as ATIVAN.

This is very strange as PGL-36 has very HIGH affinity to TSPO and would be much more potent then just 1mg Ativan.

I am waiting on production of two more substances. Olesoxime (Studies took 500mg!!!) is a pure TSPO ligand and Cholesterol derivat. It was used for ALS and Neuropathies.

Then FGIN-1-27 which showed to slow down or reverse Autoimmunity.
That's very interesting. I look forward to your next report!
 

mitoMAN

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Just ordered etifoxine (Stresam) and will see what will do for me... looks like side effects are really minimal, I want to make a practical comparison of the effects with Alprazolam (Neurol) which I had to use for sleep, but probably brought more benefits.
about 5 of us tried Etifoxine with no results. One had good results on pain management tho (With FQ Disease)

Alprazolam however only helps myself with sleep, not with energy or concentration.
 

MartinK

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@mitoMAN will see, I had good results with Alprazolam... no need sleep more than 8 hours, shorter PEM and little bit more energy/less muscle pain.
Interestingly, if something helps me, it usually affects all the symptoms - like turn volume of whole my ME/CFS to low... HBOT, L-Carnitine...and more...and last thing I suspect is a Alprazolam.
 

EddieB

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I’m not sure this is appropriate here, please forgive me if not, but y’all seem to be versed in these things.
And I’m really in trouble and need help.

My gastro symptoms have gone off the scale in the past few weeks. Stomach pain, abdominal pain, burning, pain in the throat. All symptoms of extreme acid reflux, yet past investigations show only mild inflammation/gastritis.All this has gone on alongside my ME/CFS symptoms for many years.

Doctors have suspected a visceral/ neurological cause and tried treating me with tricyclic and SSRI, but response wasn’t good.

So yesterday out of desperation I went to the emergency room. I hadn’t slept in days, the pain was unbearable, and didn’t know what else to do. I had my reservations, with covid worries it was going to be a hassle.

Finally got in saw a doctor, explained what was going on. He started an iv with a pain med and protonix.
Heavy sedation but no real relief. After a few hours of this, they gave me some liquid lidocaine, which I chocked on. Then he mentioned esophageal spasms, and gave me Ativan. Almost immediately things calmed down.
I was sent home soon after, a bit woosy the rest of the day but much better.

It’s been 24 hours now, and it feels like symptoms may be slipping back. I really feel it was the Ativan that was effective.

So my question is, what does this mean? I don’t see Ativan as being a pain killer for 24 hours. But if my real problems are anxiety/ neurological driven, is this why I’m seeing relief? Is Ativan an effective drug for visceral symptoms? I am terrified of these drugs, but this is the first thing that has helped at all.
 

EddieB

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ljimbo423

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So my question is, what does this mean? I don’t see Ativan as being a pain killer for 24 hours. But if my real problems are anxiety/ neurological driven, is this why I’m seeing relief?
Hey Eddie-

ME/CFS researcher Jarred Younger thinks that the primary cause of symptoms are from activated microglia causing neuroinflammation. Since the brain is the control center of the body, if it's inflamed, it could cause almost any symptom, including excessive pain.

I have a lot of body pain (fibromyalgia), which is also considered by Jarred Younger to be caused by neuroinflammation. My guess would be that you might be experiencing an exaggerated pain response, similar to fibromyalgia.

This is why there is so much pain but very little inflammation. My take on the ativan working, is that it's somehow lowering the neuroinflammation. Maybe by lowering microglial activation in the brain, therefore reducing inflammation in the brain and your heartburn symptoms.
 

Wishful

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My take on the ativan working, is that it's somehow lowering the neuroinflammation.
It could also be reducing the effects of neuroinflammation (cytokines, kynurenines, whatever) or the inputs to those glial cells, without actually reducing the amount of inflammation. I agree that even minor neuroinflammation can probably affect pain perception and also mess up gut function or throat function which can lead to changes that increase pain.