I wish I'd looked more carefully at this earlier but here is what I realized a few days ago. From a pharmacological standpoint it's important to know that the amount of suramin that Dr Naviaux has used for his studies is low enough that
suramin is not causing any significant antagonism at the P2X7 receptor. (Nor at P2Y2.)
Instead, it is effectively doing the opposite. Even though suramin is a P2X7 (and P2Y2) receptor antagonist, suramin in Naviaux’ studies is acting as a purinergic receptor
modulator, and it is in fact
up-regulating P2X7 (and P2Y2) - and this is indeed what Naviaux found and reported in his earlier autism mouse
study. Namely that gene expression of P2X7 (and P2Y2) increased from an original deficit to a normal level.
This purinergic receptor modulating ability of suramin is happening because of the P2X7 receptor being more difficult to antagonize than some of the other P2 receptors and because of suramin’s particular selectivities for the different P2 receptors it antagonizes, and because there is apparently a sort of sympathy or reciprocity among the P2 receptors (and other related receptors) due to crosstalk and ATP levels. When certain of the other P2 receptors are antagonized (inhibited) by suramin (or other P2 antagonists) the response at P2X7 seems to be to try to offset this, and P2X7 is up-regulated. That's my simplified interpretation of it, anyway. (P2Y2 was also similarly upregulated in the autism setting.)
(This phenomenon has been known for some time but just as a recent example, here's a
study where, like in Naviaux’ autism studies, suramin increases P2X7 gene expression thus increasing its activity despite being a P2X7 antagonist.)
So with the knowledge that suramin is actually increasing the activity of P2X7, it seems that a good reason why both the addition of extracellular ATP (a natural agonist for P2X7) and suramin have the same effect in Dr Ron Davis’ nano-needle chip device is that
they are both increasing the activity of P2X7. (Maybe Ron and his group have already realized this possibility, but just in case I'm tagging
@Janet Dafoe (Rose49) and
@Ben H.)
If this is correct, then the drug
clemastine, which is an older generation antihistamine available over-the-counter, might possibly give similar results to suramin and ATP using Ron’s device. Clemastine increases the activity of P2X7 as follows:
Clemastine Potentiates the Human P2X7 Receptor by Sensitizing It to Lower ATP Concentrations
Extracellularly but not intracellularly applied clemastine rapidly and reversibly augmented P2X7-mediated whole-cell currents evoked by non-saturating ATP concentrations. Clemastine also accelerated the ATP-induced pore formation and Yo-Pro-1 uptake, increased the fractional NMDG+ permeability, and stabilized the open channel conformation of P2X7. Thus, clemastine is an extracellularly binding allosteric modulator of P2X7 that sensitizes P2X7 to lower ATP concentrations and facilitates its pore dilation. The activity of clemastine on native P2X7 receptors, Ca2+ entry, and whole-cell currents was confirmed in human monocyte-derived macrophages. Similar effects were observed in murine bone marrow-derived macrophages. Consistent with the data on recombinant P2X7, clemastine augmented the ATP-induced cation entry and Yo-Pro-1 uptake.
(Emphasis added)
I previously mentioned clemastine
here. I'm, very preliminarily, having some good results with it myself. (This is not related to its H1 histamine-blocking ability because I regularly take two other H1 antihistamines, chlorpheniramine and diphenhydramine, and these have no effect on my ME/CFS symptoms.)
The above might also provide one explanation for a possible CD39 deficit in ME/CFS as originally hypothesized by
@necessary8 here, because increasing the activity of P2X7 increases the activity of CD39 (see, e.g., this
reference). Thus, decreased activity at P2X7 might cause decreased CD39.
Interestingly, although CD39 is seemingly needing to be increased in ME/CFS (if
@necessary8 ‘s hypothesis is correct), if you attempt to increase CD39 directly then P2X7 activity would presumably be lowered (because CD39 reduces the amount of extracellular ATP which activates P2X7) which in turn again lowers CD39 activity. So although there's seemingly a chicken and the egg situation between P2X7 and CD39 as to which one is upstream of the other, it might be that P2X7 is what needs to be addressed first in order to correct the theoretical problem at CD39 (absent an actual antibody against CD39, for example).
I'm a bit worried now, knowing the purinergic modulating ability of suramin, that any drug that only increases P2X7 may not be sufficient to fully correct things. So, for example, clemastine might need to be combined with something else to be effective. (But whether P2Y2 activity also needs to be increased in ME/CFS, like in autism, is less clear.) It may end up being the case that nothing else will work quite like suramin because of it having a broad purinergic receptor antagonism ability but yet a considerably weaker effect at P2X7, as previously noted.
FYI: Note that clemastine was recently found to be potentially very useful in multiple sclerosis. (
Reference) This, combined with many stores having already begun to phase this older antihistamine out of their lineup may make it difficult to obtain now. (As far as practical usage, this is a sedating antihistamine with a long half life so would have to be taken at night for many people.)
