Investigation into the restoration of TRPM3 ion channel activity in post COVID-19 ...,Sasso, Marshall-Gradisnik et al,2024

Discussion in 'Long Covid research' started by John Mac, Apr 10, 2024.

  1. John Mac

    John Mac Senior Member (Voting Rights)

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    Full title: Investigation into the restoration of TRPM3 ion channel activity in post COVID-19 condition: a potential pharmacotherapeutic target

    Recently, we reported that post COVID-19 condition patients also have Transient Receptor Potential Melastatin 3 (TRPM3) ion channel dysfunction, a potential biomarker reported in natural killer (NK) cells from Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) patients.

    As there is no universal treatment for post COVID-19 condition, knowledge of ME/CFS may provide advances to investigate therapeutic targets. Naltrexone hydrochloride (NTX) has been demonstrated to be beneficial as a pharmacological intervention for ME/CFS patients and experimental investigations have shown NTX restored TRPM3 function in NK cells.

    This research aimed to:
    i) validate impaired TRPM3 ion channel function in post COVID-19 condition patients compared with ME/CFS;
    ii) investigate NTX effects on TRPM3 ion channel activity in post COVID-19 condition patients.

    Whole-cell patch-clamp was performed to characterize TRPM3 ion channel activity in freshly isolated NK cells of post COVID-19 condition (N = 9; 40.56 ± 11.26 years), ME/CFS (N = 9; 39.33 ± 9.80 years) and healthy controls (HC) (N = 9; 45.22 ± 9.67 years).

    NTX effects were assessed on post COVID-19 condition (N = 9; 40.56 ± 11.26 years) and HC (N = 7; 45.43 ± 10.50 years) where NK cells were incubated for 24 hours in two protocols: treated with 200 µM NTX, or non-treated; TRPM3 channel function was assessed with patch-clamp protocol.

    This investigation confirmed impaired TRPM3 ion channel function in NK cells from post COVID-19 condition and ME/CFS patients.

    Importantly, PregS-induced TRPM3 currents were significantly restored in NTX-treated NK cells from post COVID-19 condition compared with HC.

    Furthermore, the sensitivity of NK cells to ononetin was not significantly different between post COVID-19 condition and HC after treatment with NTX.

    Our findings provide further evidence identifying similarities of TRPM3 ion channel dysfunction between ME/CFS and post COVID-19 condition patients.

    This study also reports, for the first time, TRPM3 ion channel activity was restored in NK cells isolated from post COVID-19 condition patients after in vitro treatment with NTX.

    The TRPM3 restoration consequently may re-establish TRPM3-dependent calcium (Ca 2+ ) influx. This investigation proposes NTX as a potential therapeutic intervention and TRPM3 as a treatment biomarker for post COVID-19 condition.

    https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2024.1264702/abstract
     
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  2. SNT Gatchaman

    SNT Gatchaman Senior Member (Voting Rights)

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    Now published.
     
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  3. Hutan

    Hutan Moderator Staff Member

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    A few asides before I read past the introduction (ignore if you aren't in the mood for pedantry)

    I do not like that definition. We've discussed 'complex' and 'multisystemic' before - neither are very helpful and 'complex' often leaves the door wide open for a psychological contribution to etiology. What is 'complex' actually saying there? If people want to say that there are a number of symptoms, it's probably more helpful to list some of them e.g. 'with a number of symptoms including ...'. I have no idea what 'post-exertional neuroimmune exhaustion' is - I assume it is used because it sounds as though someone knows something. But I'm not just exhausted when I have PEM, and I don't know if my neuroimmune system is exhausted either. This description emphasises fatigue. And we've talked about 'not alleviated by rest' as being problematic too, as resting does actually reduce fatigue in a way that 'not resting' does not. Maybe 'chronic fatigue not resolved by rest' would be better?

    Oddly, the term post-exertional malaise is used too but it is not defined - this is the paragraph before paragraph quoted above:
    I'm pretty sure that is a typo there. There are quite a lot of instances of clunky language that make the paper harder to read. I understand the difficulties of writing in a language that isn't your first language, possibly that was the case here. But supervisors who are native English speakers and who have been co-authors on ME/CFS papers for years should be providing more support so that we get papers that do justice to the effort that was expended on the lab work.

    I don't think 30% of people having a SARS-CoV-2 infection and then not returning to their prior state of health is credible.
     
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  4. Hutan

    Hutan Moderator Staff Member

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    It's yet another study with small numbers in the groups.

    We have discussed the difficulty of characterising NK cell function before. Blood samples were collected from many places, with a full blood count completed within 4 hours at labs that are not NCNED. But, the authors do not say how long it was before the samples got to NCNED and the isolation of the NK cells and subsequent analyses were done.
    I've just made a thread for a paper that suggests a protocol for evaluating NK cell cytotoxicity. Flow Cytometric Analysis of Natural Killer Cell Lytic Activity in Human Whole Blood, 2017, McBride et al That paper says talks about a four hour window from blood collection for evaluation, although it does not present new evidence for that assertion. So, that's not just 4 hours from collection to full blood count, but 4 hours from collection to cytotoxicity evaluation (and any experiments reliant on NK cell function).
     
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  5. Andy Dearden

    Andy Dearden Established Member

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    But perhaps this study can be used to justify a more rigorous replication study to explore this TRPM3 idea as a key lab-based diagnostic marker?
     
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  6. Hutan

    Hutan Moderator Staff Member

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    Sure, but we never see such well-powered and definitive studies out of NCNED. They have received a lot of the Australian ME/CFS funding, probably more than any other group. From here, it's hard to know if the funds are being used well. I do think that it's questionable to keep doing small, possibly flawed, studies based on the foundation of the TRPM3 finding without proving beyond all doubt that there is a real abnormality there.
     
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