Selective translocator protein (TSPO) agonists

leokitten

leokitten

Senior Member (Voting Rights)
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. 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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Hutan said:
This thread
How Might Ativan, Clonazapem Increase Strength?
seems relevant, at least for answering the first question I had, which was 'is there fairly strong anecdotal evidence of lorazepam improving ME symptoms?'. Several members (at the severe end of the ME/CFS spectrum) have reported benefits from similar drugs.
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I read that clorazepam (Klonopin) has no affinity for the TSPO/PBR receptor. Have severe patients reported the same significant temporary improvement from clorazepam as for lorazepam? That would help answer one of the questions I wrote in the OP.
 
It might be useful to get a sense for how many patients the anecdotal evidence holds true? It's so easy to get a skewed idea of the extent of the impact.

I have two friends with ME who, like me, have been prescribed lorazepam. It had exactly the effect you'd expect: feeling weak, drugged, sleepy, and unresponsive.

I took it for several years – I was given it as a teenager, without any warning that it was extremely addictive as well as completely inappropriate for someone not suffering any symptoms that warranted its use. Unsurprisingly, my ME symptoms improved a great deal after managing to withdraw from it. The friend who used it for dental treatment found it made her feel so awful that it was preferable to conquer her phobia.

These are only anecdotes, of course, but they ought to be weighed against those from people who feel better. It may be relevant that only one of the friends I mention has severe ME – the other two tend to slide up and down the mild/moderate scale over time.
 
Kitty said:
It might be useful to get a sense for how many patients the anecdotal evidence holds true? It's so easy to get a skewed idea of the extent of the impact.
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Yes totally, maybe too when a person deteriorates to severe or very severe ME the pathophysiology takes on new aspects, and lorazepam might only benefit here.
 
There is some discussion in this paper about the future of constructing neuropsychotropic drugs in the series of TSPO ligands (I've only read the abstract)
https://pubmed.ncbi.nlm.nih.gov/32881658/
In 2020, it is already 43 years since Braestrup and Squires discovered 18 kDa translocator protein (TSPO), known until 2006 as 'peripheral benzodiazepine receptor'. During this time the functions of this receptor which is located on the outer membrane of mitochondria were studied in detail. One of the key functions of TSPO is the transfer of cholesterol from the outer to the inner mitochondrial membrane, which is the limiting stage in the synthesis of neurosteroids. TSPO is also involved in the transport of porphyrins, mitochondrial respiration, the opening of mitochondrial pores, apoptosis and cell proliferation. This review presents current information on the structure of TSPO, the mechanism of its participation in neurosteroidogenesis, as well as endogenous and synthetic TSPO ligands. Particular emphasis is placed on the analysis of approaches to the design of synthetic ligands and their neuropsychotropic activity in vitro and in vivo. The presented review demonstrates the promise of constructing new neuropsychotropic drugs in the series of TSPO ligands.
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Jonas Berquist has done steroidomics in ME/CFS and presented at the Stanford Symposium and elsewhere on the topic. I don't think it's published info.
https://www.omf.ngo/second-annual-symposium-transcripts/
What we found is, maybe not dramatic changes but we have changes that I think are relevant when we come to discussion of what's going on in the patient group. So if I have a general downregulation of many of the steroids, the only one that came out significant, as you see here, is pregnenolone. I will show you what that can mean. Pregnenolone is the key steroid in the biochemical pathway. So it's actually the precursor of the rest of the steroid profiles.
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. I also put these blue arrows in the biochemical pathway here. All of these enzymatic ways that I marked here are located to a specific organelle. Is there anybody who can guess what organelle that is? Mitochondria. So pregnenolone is one of the neurotransmitters that are neurosteroids that we have in very high concentrations in the brain.
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Many papers describe how TSPO is involved in this pathway.
 
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