Selective translocator protein (TSPO) agonists

leokitten

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Given that there is anecdotal evidence of lorazepam (Ativan) causing rapid temporary improvement of ME symptoms, even in very severe cases, I’ve wondered why ME researchers aren’t looking more closely at researching selective translocator protein (TSPO) agonists. TSPO is also known as the peripheral benzodiazepine receptor (PBR) and is primarily found on the inner and outer mitochondrial membrane.

A few selective TSPO/PBR agonist compounds exist in research, and they do not have affinity for the central GABAA receptor, therefore they do not have the negative effects benzodiazepines have, so drugs selectively targeting TSPO could potentially be taken long term.

A few examples are Ro5-4864, Emapunil, and SSR-180,575

By researching these compounds in ME/CFS we could discover if indeed the effect lorazepam has on ME symptoms is due to TSPO agonism and the resulting effects on mitochondria, glial cells, adrenals and steroids, inflammation, etc. and not due to central GABAA binding. EDIT: In addition, these could be a tool to help us understand the pathophysiology of ME and a potential target for ME/CFS treatment and drug development.
 
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leokitten

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Dear @Janet Dafoe - just pinging you in case you have time to see this, wondering if Ron and OMF are looking at selective TSPO agonist compounds to research their effect in ME/CFS. I feel these could help us understand the pathophysiology of ME and a potential target for ME treatment.
 
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Wishful

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It might only be altering the immune response, which in turn might modulate whatever immune activation is increasing your ME symptoms. If so, it might help some people, but not treat the underlying problem of ME. They should identify how it's working before investing heavily in trying to turn it into a treatment.
 

leokitten

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It might only be altering the immune response, which in turn might modulate whatever immune activation is increasing your ME symptoms. If so, it might help some people, but not treat the underlying problem of ME. They should identify how it's working before investing heavily in trying to turn it into a treatment.
Good point, I should’ve also mentioned that using selective TSPO agonist compounds in ME experimental research might also help us understand at least part of the pathophysiology of ME.
 
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Wishful

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I'm certainly in favour of experiments. I certainly can't say that TSPO agonists won't affect ME. I just don't get too excited when something helps one person and has a theory for why it works, but the substance has many different effects, so that particular theory may not apply. Things that do help one (or preferably more than one) PWME should indeed be checked further to try to figure out why.
 

Hip

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Given that there is fairly strong anecdotal evidence of lorazepam (Ativan) causing rapid temporary improvement of ME symptoms
I have not come across this before. Is it only lorazepam that has this effect, or all benzodiazepines?

Coincidently, I was just planning to buy an anti-anxiety drug called etifoxine, which I see is on the Wikipedia list of TSPO agonists. Etifoxine is cheap and available at some of the Russian online pharmacies, like RUPharma and ExtraPharmacy.


Note that in the Myhill studies, they found TSPO function ANT function was compromised in ME/CFS patients.
 
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Hip

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Are you sure that the Myhill studies were talking about "translocator protein" (TSPO), and not "adenine nucleotide translocator" (ANT)? (The two might interact with each other, though.)
Sorry, yes you are right. I was getting confused.

The Myhill group found the adenine nucleotide translocator (ANT) was compromised in ME/CFS patients, rather than the translocator protein (TSPO).

Confusingly, in their published studies, the Myhill group refer to ANT as the "translocator protein".


I believe both ANT (found on the inner mitochondrial membrane) and TSPO (found on the outer mitochondria membrane) work in tandem to ferry ATP out of the mitochondria.
 

leokitten

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I have not come across this before. Is it only lorazepam that has this effect, or all benzodiazepines?
Only certain benzodiazepines have affinity for the TSPO receptor (in addition to GABAA receptor, which all do) and the ones that do bind TSPO have varying affinities and intrinsic activities, same as for other drugs targeting a specific receptor.

Clorazepam for example has almost almost no affinity. Lorazepam, diazepam, and flumazenil for example have affinity for TSPO. I couldn’t find exact Ki for lorazepam, but I believe it’s the strongest, and for the three examples I listed TSPO affinity = lorazepam > diazepam > flumazenil. I’ll try to look for more info on others.
 

Hip

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People have anecdotally said etifoxine can have significant side/adverse effects.
Yes, apparently there is a liver injury risk.

Though intriguingly, etifoxine has been found to be "remarkably efficient in promoting acceleration of peripheral nerve regeneration and functional recovery".

I wonder if that might help autonomic dysfunction in ME/CFS.
 

mitoMAN

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A TSPO ligand is protective in a mouse model of multiple sclerosis

https://www.embopress.org/doi/pdf/10.1002/emmm.201202124
Our results showed that etifoxine attenuated experimental autoimmune encephalomyelitis (EAE) severity when administered before the development of clinical signs and also improved symptomatic recovery when administered at the peak of the disease. In both cases, recovery was correlated with diminished inflammatory pathology in the lumbar spinal cord. Modulation of TSPO activity by etifoxine led to less peripheral immune cell infiltration of the spinal cord, and increased oligodendroglial regeneration after inflammatory demyelination in EAE. Our results suggest that a TSPO ligand, e.g. etifoxine, could be a potential new therapeutic option for MS with benefits that could be comparable to the administration of systemic steroids but potentially avoiding the detrimental side effects of long-term direct use of steroids
 

bread.

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Took 4 dosages so far (50mg per day):
The first dose of Etifoxine gave a subtle energy boost while I noticed the following three dosages made me very tired.
I might switch over to taking the Etifoxine before bedtime.
As of now I will pause for a few days to compare to my baseline level and re-evaluate.
you are a fucking beast bro, stay safe please.
 

pattismith

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Only certain benzodiazepines have affinity for the TSPO receptor (in addition to GABAA receptor, which all do) and the ones that do bind TSPO have varying affinities and intrinsic activities, same as for other drugs targeting a specific receptor.

Clorazepam for example has almost almost no affinity. Lorazepam, diazepam, and flumazenil for example have affinity for TSPO. I couldn’t find exact Ki for lorazepam, but I believe it’s the strongest, and for the three examples I listed TSPO affinity = lorazepam > diazepam > flumazenil. I’ll try to look for more info on others.
it may be easy to check if patients reporting improvement with Ativan improve because of the GABA-A effect or the TPSO effect.... just trying other benzos with zero TPSO effect?
 

leokitten

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it may be easy to check if patients reporting improvement with Ativan improve because of the GABA-A effect or the TPSO effect.... just trying other benzos with zero TPSO effect?
Yes totally, I asked Janet Dafoe about to Whitney doesn’t have nearly the same effect from clonazepam, which is just as strong at the GABA-A receptor as lorazepam but has almost no affinity for TSPO.