R. Anne Teaze 🥄🦓 🕊️

For MCAS and Long COVID, Japan has a Solution called Ketas (ibudilast) since 1989. The same thing is now in Western trials for neuroinflammatory disease. Ketas is a brain-penetrant inhibitor of PDE4 (phosphodiesterase 4, the enzyme that breaks down cAMP in immune cells) and PDE10 (phosphodiesterase 10, which breaks down cAMP and cGMP in neurons), with additional activity at PDE3 and PDE11, two more enzymes that clear the same cyclic nucleotides. It is also an allosteric inhibitor of MIF (macrophage migration inhibitory factor, a cytokine that keeps inflammation from resolving) and an antagonist at TLR4 (toll-like receptor 4, the sensor for endotoxin and damage signals). Japan approved it for asthma and for dizziness tied to poor cerebral blood flow. The FDA has not approved it. MediciNova runs it as MN-166, with Fast Track and orphan status in ALS (amyotrophic lateral sclerosis), and it has been taken into lingering-COVID protocols for the same glial and cytokine reasons. MCAS: Mast cells keep cAMP (cyclic adenosine monophosphate, the signal that tells the cell to stay quiet) low through PDE4. Low cAMP favors degranulation, TNF (tumor necrosis factor, a core inflammatory cytokine), IL-6 (interleukin-6, the fever and fatigue cytokine), and the leukotriene arm. Ibudilast raises cAMP by blocking that enzyme, so the cell is less willing to dump. Older pharmacology also gives it leukotriene-receptor antagonism, which is the part an H1 blocker (histamine H1 receptor blocker) never covers. MIF is released by mast cells and then calls more inflammation in. Blocking MIF shortens that loop. TLR4 is how endotoxin and mold fragments prime the mast cell before a food arrives. Ibudilast antagonizes TLR4 and cuts the MyD88 (the adaptor that carries the TLR4 signal inward) and NF-kB (nuclear factor kappa B, the transcription switch for inflammatory genes) traffic underneath it. Long COVID: The persistent form is not a missing antihistamine. It is microglia that stayed on, TLR4 still ligated by residual inflammatory signals, and mast cells firing on a lowered threshold. Ibudilast crosses into the brain, suppresses glial activation, and raises cerebral blood flow. That is the cognitive half: processing speed and the wired-but-exhausted feeling track perfusion and glial noise more than they track dopamine. MIF and TLR4 are the systemic half. They keep the cytokine set point high after the virus is gone. PDE4 blockade in immune cells pulls TNF, IL-1β (interleukin-1 beta, the inflammasome cytokine), and IL-6 down. People whose long COVID looks like MCAS, POTS-adjacent flares (postural orthostatic tachycardia, the heart-rate jump on standing), brain fog, and post-exertional inflammatory crashes are the overlap this molecule was built for, even though the Japanese label never used those words.