Montelucast against Brainfog in LongCovid

The patient suffered from the viral persistence form of Long Covid – 17 months of sick leave – then quickly improved physically with Iver-xx, but persistent brain fog that sets in after about 15 minutes of mentally demanding work (with blurred vision and dizziness).

• After the first Montelucast dose: 80% improvement
• On the 2nd day: 100% improvement in brain fog

She wishes to remain anonymous (including her voice), so this is an anonymous testimonial video – but she would like this experience to be shared with other doctors and those affected.

OK, here is my relevant study research

Montelukast attenuates microglial activation and neuroinflammation – Evidence for clinical practice

Summary

Montelukast, a CysLT₁ receptor antagonist, inhibits microglial activation in preclinical models, reduces proinflammatory cytokines (e.g., IL-1β, TNF-α), modulates NF-κB/NLRP3 signaling pathways, and promotes M2 microglia polarization. Initial clinical data demonstrate good safety and CNS exposure, as well as proteomic evidence of anti-inflammatory effects. Overall, a growing body of data supports its use as a repurposing candidate for neuroinflammation prevention. (MDPI, PMC, ScienceDirect)

Pathophysiological background

• Leukotriene axis in microglia: Cysteinyl leukotrienes via CysLT₁/CysLT₂ activate, among other things. NF-κB and NLRP3, thus driving microglia-mediated neuroinflammation. Blockade by montelukast interrupts this cascade. (MDPI, PMC)

Key Studies (Selected)

• Aging Brain (Rat): Chronic Montelukast Administration reduces microglial activation, increases neurogenesis, and improves cognition. This is considered an early, frequently cited proof of concept for microglial modulation. (PMC)
• Alzheimer’s models (mouse): Long-term treatment reduces neuroinflammatory markers and improves cognitive parameters in transgenic AD mice; in addition, a recent study shows age-dependent effects with significant reduction in inflammation in younger APP/PS1 mice. (PMC, Nature)
• Striatal neurotoxicity (rat): In the quinolinate model, montelukast reduces neuroinflammation (immunofluorescence) and preserves metabolic connectivity. (BioMed Central)
• Parkinson’s disease models (mouse/rat):
  • 6-OHDA model: Protection of dopaminergic neurons by attenuation of microglial cytokines (TNF-α, IL-1β) in the substantia nigra and striatum. (PubMed)
  • Rotenone model: Neuroprotection with an anti-inflammatory profile, consistent with microglial attenuation. (PubMed)
• Ischemia (mouse): Microglial polarization towards M2, less infarction/inflammatory response under montelukast. (ScienceDirect)
• Molecular Hubs: Preclinical evidence of NLRP3/IL-1β arm inhibition and NF-κB silencing under montelukast. (ScienceDirect)

Clinical and Translational Data

• Parkinson’s Disease Patients (Phase 2a, High-Dose): Montelukast is safe, crosses the blood-brain barrier at low concentrations; CSF proteomics showed changes compatible with inflammatory modulation. (PMC, movementdisorders.onlinelibrary.wiley.com)
• Alzheimer’s Disease: Ongoing Randomized, Placebo-Controlled Trial> (NCT03991988) is testing clinical efficacy; the primary mechanism targets neuroinflammation/microglia. (Clinical Trials)
• Evaluation of reviews: Reviews summarize the CysLT signaling pathways in microglia and consider CysLT antagonists (including montelukast) to be promising against neuroinflammatory processes. (MDPI, ScienceDirect)

Clinical Implications for Physicians

• Target Structure: Microglia and downstream NF-κB/NLRP3 pathways are key targets; Montelukast exhibits anti-inflammatory and neuroprotective effects in several disease models. (ScienceDirect, MDPI)
• Translation: Preclinical consistency across AD, Parkinson’s, ischemia, and toxic models suggests that montelukast can be considered as an add-on for neuroinflammation control in clinical programs; definitive evidence of efficacy in large trials is pending. (PMC, ScienceDirect, Clinical Trials)
• Safety/Exposure: Initial human data demonstrate good tolerability and CNS exposure; this supports the feasibility of anti-inflammatory strategies via the leukotriene axis. (PMC)

Take-home message

Montelukast uncouples microglia-driven neuroinflammation at multiple signaling switches, with robust preclinical evidence (microglial activation ↓, cytokines ↓, M2 shift ↑) and early clinical data on safety and biological plausibility. The ongoing RCTs will clarify in which indications microglial modulation by montelukast will be clinically useful. (PMC, PubMed, ScienceDirect, Clinical Trials)

Further references for the website appendix: Reviews on CysLT receptors in neurodegeneration and Montelukast repurposing provides a concise overview of the mechanism and the current state of evidence. (PMC, MDPI)