The Spike Protein, H1 Receptors and Long COVID

How intranasal chlorpheniramine’s success in treating Long COVID may show us a key CNS pathogenic mechanism of the Spike Protein.

Clinical outcomes, Placebo vs., iCPM

A study published last week (Nov. 26^th) showed that intranasal chlorpheniramine (iCPM, a histamine receptor H1 antagonist) was quite effective in alleviating symptoms of Long COVID.

Findings

The iCPM cohort had a lower proportion of patients with fatigue or tiredness vs. placebo (0 Vs 17, 21, p < 0.001). iCPM cohort had a lower proportion of patients with difficulty concentrating or mental confusion (0 vs. 22, 27, p < 0.001). iCPM cohort had also a lower number of patients with difficulty in the ability to perform daily activities or work vs. placebo (1 Vs 38, 48, p < 0.001). A smaller number of patients in the iCPM cohort sought medical attention for PACS symptoms compared to placebo (0 vs. 48, 68, p < 0.001).

Interpretation

The use of intranasal chlorpheniramine shows promise in preventing COVID-19 progression to the often-debilitating post-COVID-19 syndrome PASC. The association between iCPM use and a lower prevalence of PASC symptoms is strong. Further studies are needed to establish the role of ICPM in preventing PASC.

But, if we are looking at Spike Protein pathology, what iCPM did NOT do is perhaps just as telling what it DID.

Joint or muscle pain did not differ significantly between the iCPM and placebo groups (0 out of 139 vs. 3 out of 120, 3.5, p = 0.06).

Mitigating the risks of post-acute sequelae of SARS-CoV-2 infection (PASC) with intranasal chlorpheniramine: perspectives from the ACCROS studies
https://link.springer.com/article/10.1186/s12879-024-10211-8

The point being, iCPM alleviated NEUROLOGICAL symptoms. Why is this so important? Because the nasal epithelium is almost certainly a reservoir (Spike Factory) for SARS-CoV-2 and its Spike Protein.

In this study, the long-term dynamics of SARS-CoV-2 infection were investigated using a human well-differentiated nasal epithelial cell (NEC) model of infection. NECs were observed to release SARS-CoV-2 virus onto the apical surface for up to 28 days postinfection (dpi), further corroborated by viral antigen staining. Single-cell transcriptome sequencing (sc-seq) was utilized to explore the host response from infected NECs after short-term (3-dpi) and long-term (28-dpi) infection. We identified a unique population of cells harboring high viral loads present at both 3 and 28 dpi, characterized by expression of cell stress-related genes DDIT3 and ATF3 and enriched for genes involved in tumor necrosis factor alpha (TNF-α) signaling and apoptosis. Remarkably, this sc-seq analysis revealed an antiviral gene signature within all NEC cell types even at 28 dpi. We demonstrate increased replication of basal cells, absence of widespread cell death within the epithelial monolayer, and the ability of SARS-CoV-2 to replicate despite a continuous interferon response as factors likely contributing to SARS-CoV-2 persistence.

Human Nasal Epithelial Cells Sustain Persistent SARS-CoV-2 Infection In Vitro, despite Eliciting a Prolonged Antiviral Response
https://pmc.ncbi.nlm.nih.gov/articles/PMC8764519/

Yes, the fact that iCPM reduces inflammation, etc. Is wonderful. What is better is that it outcompetes the Spike Protein for H1 receptor attachment. For those who are not aware, the H1 receptor is also a Spike Protein receptor.

We and others have found that antihistamine drugs, particularly histamine receptor H1 (HRH1) antagonists, potently inhibit SARS-CoV-2 infection. In this study, we provided compelling evidence that HRH1 acts as an alternative receptor for SARS-CoV-2 by directly binding to the viral spike protein. HRH1 also synergistically enhanced hACE2-dependent viral entry by interacting with hACE2. Antihistamine drugs effectively prevent viral infection by competitively binding to HRH1, thereby disrupting the interaction between the spike protein and its receptor.

The histamine receptor H1 acts as an alternative receptor for SARS-CoV-2
https://pmc.ncbi.nlm.nih.gov/articles/PMC11324024/

The olfactory nerve is a direct route to the brain. H1 receptors are there on the olfactory receptor neurons!

Results

We demonstrated that mRNAs encoding histamine H1, H2, and H3 receptors were detected in rat olfactory epithelium. Immunohistochemistry also showed strong positive staining for these receptors. Co-localization of histamine H1, H2, and H3 receptors with olfactory mature protein revealed that these three histamine receptors were mainly localized in olfactory receptor neurons.

Conclusions

These findings indicate that histamine H1, H2, and H3 receptors are present in rat olfactory epithelium and may play a physiological role in olfactory transmission.

Expression and localization of histamine H1, H2, and H3 receptors in rat olfactory epithelium
https://www.sciencedirect.com/science/article/abs/pii/S0165587617303646

The Spike Protein’s interaction with H1 receptors in the brain offers insight into the above discussed symptoms in those with Long COVID.

Histamine is a signaling molecule in the immune system, the skin, the stomach, and the brain of vertebrates. Histaminergic neurons are located exclusively in the tuberomamillary nucleus of the posterior hypothalamus and extend their axons throughout the central nervous system. These neurons are active during the awake state but not during sleep. Three of the four known histamine receptors are widely expressed in the brain. H1 and H2 receptors are mostly excitatory and H3 is an inhibitory auto- and heteroreceptor. Close mutual interactions between histaminergic and other aminergic and peptidergic systems form a network with basic homeostatic functions, including sleep–wake regulation, feeding, drinking, synaptic plasticity, learning, and memory.

Sleep and Sleep States: Histamine Role
https://www.sciencedirect.com/science/article/abs/pii/B9780080450469000346

Beyond the neurological implications for Long COVID, what else does the iCPM study show us? It may be showing us what many of us have known from the beginning: Constant exposure to the Spike Protein disrupts virtually every process in the body.

Thank you, as always for your readership, dialog and support. I will search for additional therapeutics which may assist us in keeping the Spike Protein out of our CNS and out of bodies in general.