Could mast cell stabilizer CROMOLYN reduce neuroinflammation & improve cognitive function in some cases of Long Covid & ME/CFS?
A brief exploration into the relationship b/t mast cells, microglia, & neuroinflammation, and how cromolyn (available Rx&OTC) might reduce symptoms.
Mast cells release inflammatory molecules in response to pathogens which in turn activates microglia, the primary neuroimmune cells in the CNS. Microglia make up ~5-20% of total brain cells. They secrete cytokines (notably TNF-α) & chemokines in response to changes.
This 2021 study found that microglial activation was the most common brain pathology found in deceased COVID patients (42.9%, or 79 in 184). (15% had microclots in brain tissue.)
This June 2022 preprint presents in-vivo evidence of widespread neuroinflammation in two Long Covid sufferers. While this is a tiny sample size, authors explain the very first 2 participants studied showed neuroinflam & so they wanted to release data ASAP.
The two LC pts were compared to 3 non-infected healthy controls. Disturbingly, PET imaging revealed that the neuroinflamm appeared even MORE widespread than in post-mortem brain tissue! Notably, the thalamus was affected, likely contributing to fatigue & cognitive disabilities.
Thus it appears that the following may occur for some with Long Covid (& perhaps those w/ ME/CFS considering similarities).
mast cell activation syndrome (MCAS)
How can we turn off--or at least dampen--this process?
CROMOLYN inhibits sensitized mast cell degranulation which in theory should
microglia & inflammatory cytokines. But does it?
This 2021 study tested cromolyn's ability to dampen microglial pro-inflammatory responses in HMC3 microglia cell lines. pubmed.ncbi.nlm.nih.gov/33850164/
The authors induced microglia activation by the inflammatory cytokine TNF-α and then compared the effects of cromolyn vs control.
They found that indeed, cromolyn at 3µM significantly inhibited inflammatory cytokines & chemokines secreted by microglia.
Not only did cromolyn reduce levels of IFN-y, IL-6, IL-1ß & IL-8 by 47%, 40.5%, 49.3%, & 25.8%, respectively, but the drug also significantly reduced their relative gene expression and prevented HMC3 microglia cell death induced by TNF-α in a concentration-dependent manner.
This 2017 mouse study found likewise reductions in inflammatory cytokines by cromolyn. Authors concluded: "Interactions between mast cells and microglia could constitute a new and unique therapeutic target for CNS immune inflammation-related diseases. pubmed.ncbi.nlm.nih.gov/26797518/
Soon thereafter, a 2018 mouse study pub. in Nature concluded that cromolyn induced a "neuroprotective microglial activation state favoring Aβ phagocytosis versus a pro-neuroinflammatory state." This also aligns with the results from the 2021 study.
Inspired by the in vitro & mouse studies, several human trials are currently underway investigating the neuroprotective and anti-inflammatory effects of cromolyn in covid pneumonia and Alzheimer's disease.
Before the large Alzheimer's trial began, a study was performed to investigate the pharmacokinetics, safety & tolerability of cromolyn (single inhaled dose 17.1 mg; double dose 34.2 mg) & ibuprofen co-administration. pubmed.ncbi.nlm.nih.gov/28856569/
The study showed average maximum concentrations in the CSF of 0.24 ± 0.08 ng/ml & 0.34 ± 0.17 ng/ml after single- & double-doses, respectively. Unfortunately, this converts to a *significantly* lower molarity than the 0.3µM & 3 µM tested in vitro.
In summary, cromolyn may dampen neuroinflamm & improve cognitive function, although formulations w/
bioavailability may be required for sig benefits. Cromolyn trials are underway in AD & Covid. Aspects of "brain fog" in LC have drawn comparisons to AD. ncbi.nlm.nih.gov/pmc/articles/P…
A trial of cromolyn may be warranted in some--esp those w/ MCAS. Cromolyn is available OTC in the US as a nasal spray. Its onset of action is typically 2-6 weeks (so trial should last at least that long) & it should be taken every 4-6 hrs for full effects. ncbi.nlm.nih.gov/books/NBK55747…
CORRECTION: onset of action is actually even faster via nasal route: **1-2 weeks** vs 2-6 wks oral administration.