Discussion in 'BioMedical ME/CFS Research' started by Andy, Apr 25, 2019.
Open access at https://molmed.biomedcentral.com/articles/10.1186/s10020-019-0083-4
Another tiny study from the Griffith team. I hope their increased funding will mean they can do much bigger validation studies, and preferably other people do validation studies too.
what funding is this?
when will we find out where this recently-publicised Aus Government money will go?
I'm pretty sure the Griffith Uni team have managed to get a lot of funding from somewhere. Can't remember where - a charity I think.
Combination of charities and state level government grants. The most recent federal level government grant hasn't be allocated to anyone yet as far as I'm aware.
For easier reading
Chronic Fatigue Syndrome/ Myalgic Encephalomyelitis (CFS/ME) is a complex multifactorial disorder of unknown cause having multi-system manifestations.
Although the aetiology of CFS/ME remains elusive, immunological dysfunction and more particularly reduced cytotoxic activity in natural killer (NK) cells is the most consistent laboratory finding.
The Transient Receptor Potential (TRP) superfamily of cation channels play a pivotal role in the pathophysiology of immune diseases and are therefore potential therapeutic targets.
We have previously identified single nucleotide polymorphisms in TRP genes in peripheral NK cells from CFS/ME patients.
We have also described biochemical pathway changes and calcium signaling perturbations in NK cells from CFS/ME patients.
Notably, we have previously reported a decrease of TRP cation channel subfamily melastatin member 3 (TRPM3) function in NK cells isolated from CFS/ME patients compared with healthy controls after modulation with pregnenolone sulfate and ononetin using a patch-clamp technique.
In the present study, we aim to confirm the previous results describing an impaired TRPM3 activity in a new cohort of CFS/ME patients using a whole cell patch-clamp technique after modulation with reversible TRPM3 agonists, pregnenolone sulfate and nifedipine, and an effective TRPM3 antagonist, ononetin.
Indeed, no formal research has commented on using pregnenolone sulfate or nifedipine to treat CFS/ME patients while there is evidence that clinicians prescribe calcium channel blockers to improve different symptoms.
Whole-cell patch-clamp technique was used to measure TRPM3 activity in isolated NK cells from twelve age- and sex-matched healthy controls and CFS/ME patients, after activation with pregnenolone sulfate and nifedipine and inhibition with ononetin.
We confirmed a significant reduction in amplitude of TRPM3 currents after pregnenolone sulfate stimulation in isolated NK cells from another cohort of CFS/ME patients compared with healthy controls.
The pregnenolone sulfate-evoked ionic currents through TRPM3 channels were again significantly modulated by ononetin in isolated NK cells from healthy controls compared with CFS/ME patients.
In addition, we used nifedipine, another reversible TRPM3 agonist to support the previous findings and found similar results confirming a significant loss of the TRPM3 channel activity in CFS/ME patients.
Impaired TRPM3 activity was validated in NK cells isolated from CFS/ME patients using different pharmacological tools and whole-cell patch-clamp technique as the gold standard for ion channel research.
This investigation further helps to establish TRPM3 channels as a prognostic marker and/ or a potential therapeutic target for CFS/ME.
NK cells research in 2019
Tbh its a little hard to read without the relevant education, but i saw on wiki that TRMPM3 is assumed to modulate glucose homeostasis, so if they found that it`s impaired in NK cells could it just be that its a downstream effect related to energy failure like we find elsewhere?
I’m not up to reading details but I’m interested whenever a different medication gets mentioned. I looked up nifedipine on Wikipedia and it seems to be quite an old medication which isn’t widely used for hypertension as ones like amlodipene have been shown to be more effective/less side effects although it is used for some more specific issues.
I’m just wondering why this specific medication is being used. Obviously amlodipene hasn’t made any difference to my ME & I’ve been taking it for years. Apologies if this is irrelevant comment.
I too was wondering about this. I have developed high BP in recent years for which I receive treatment although in early years of ME, BP was very low especially early in the morning. The low blood pressure was a surprise because although when doing a 24 hour test the results were normal, I did have a tendency for BP to rise and I had quite severe preeclampsia ( hospitalised for a month) during a first pregnancy.
My BP drugs need adjusting, and while nifedipine is an old drug superseded by others,( I looked it up too) the obvious question for me is whether it could be used with a double purpose. I expect it doesn’t work like this but can anyone explain why? I am probably being very ignorant.
Any thoughts on this folks?
Dr Helene Cabanas and the NCNED research teams important publication success: https://www.ncbi.nlm.nih.gov/pubmed/31014226
Pathology of CFS/ME - TRPM3 Biomarker and pathology confirmed to be significantly impaired in another independent CFS/ME cohort using the drug nifedipine.
1. Impaired TRPM3 activity for potential biomarker was further validated in NK cells isolated from CFS/ME patients
2. These results for identification of pathology have been confirmed in a new cohort of CFS/ME patients and healthy participants.
3. NCNED Researchers used nifedipine, a known drug used by CFS/ME patients and a reversible TRPM3 agonist to treat NK cells from CFS/ME patients.
4. Nifedipine, confirmed a significant loss of the TRPM3 channel activity in CFS/ME patients and pathology of this family of receptors in this illness.
5. TRPM3 is not only confirmed in the pathology of CFS/ME but now considered as a potential biomarker and targeted for treatment for CFS/ME
6. NCNED is now trialing other drugs to target TRP channels for benefiting CFS/ME patients.
Please note: The criteria used by the Aussies to select the patients was the ICC.
I'd also be interested in why they chose that calcium channel blocker.
Several years ago I was a on a different one to what I have ended up on (currently amlodipine) and it did seem to both reduce background pain levels and make me more functional. I was taking it intermittently until I noticed this. When mentioned to a doctor they basically took the piss in an official report, implied that I was clearly barking because I thought this.
Amlodipine does squat regarding my ME, but the previous calcium channel blocker, made a difference.
Yup. I need to check one of my drugs to see if it is a calcium channel blocker. Hang on.....
Neither are. Hmm.
Well, it probably doesn’t work like this. Your experience was interesting though @Wonko.
Ron Davis has talked about repurposing old drugs........
One can just hope.
How is an isolated calcium mobilisation defect proof of autoimmunity?
I find that explanation somewhere else ( I can't find it now) but in general it says: NK cells to be activated need Ca signaling. Other words: if Ca does not enter the NK cells it cannot be activated. What activated means? Simply such cell know who is the enemy. Non activated cells can go around and attack anything even own tissue. And there are many of them cause some virus or something else iniciate their multipication. That is why autoimmunity is always "because of something" , don't start just by itself. Hope this is clear enough. I am not native English speaker, I understand you all, but my writting is little bit a problem.
Thank you so much for your reply Neli. I think that I understand your writing perfectly, you should be proud of your English, not apologising!
So what I am taking from this is that NK cell "activation" (memory maybe? I am not great with the immune system!) is calcium signalling dependent, and that when "inactive" they cannot distinguish pathogen from self and you get autoimmunity?
Assuming that this very shallow interpretation of mine without further reading is correct (a big assumption!) my next question would be... What is the degree of calcium signalling impairment needed to induce such a dysfunctional phenotype? Is a TRPM3 defect alone enough to result in this (it is not the only calcium channel), and if so, what is even the quantitative extent of this defect? Not in terms of patch-clamp output but relative to the cell's actual stoichiometric demand for calcium mobilisation. Questions I suspect beyond the scope of the study
Let's have some knock-outs and targeted phenotypic assessments based on these theories. That's what this naive observer would like to see.
I will follow up with reading when I am free of a foggy brain !!
First thank you for my English evaluation. I am at ease now, I will write more freely. Second, I guess what you ask yourself, scientist are asking right now, so: good question. What I figured out: what they found is an link to autoimmunity. Now they are proving it. If it is deficiency it can be cured . If it is defect, they must find what is the cause of it ( what damaged it). I like to put things simple this way. Than I wait for next research.
Prof Marshall-Gradisnik, Prof Staines, Dr Cabanas and the NCNED Team at Griffith University provided an update on their ion channel findings and drug trials:
TRP = Transient Receptor Potential ion channels
TRPM3= Transient Receptor Potential Melastatin 3 ion channels
Congratulations and much Gratitude from Canada!
My wife would freak if ME/CFS proves to be a channelopathy. She would think I'm encroaching on her space - although technically hers is a potassium channelopathy, not calcium.
I must admit the overlap in symptoms can be, at times, striking.
Separate names with a comma.