foggynotion | 12 points | Jul 23 2020 16:10:53

Since people are still studying the efficacy of ivermectin with SARS-CoV-2 I thought I'd post a couple research papers I think lay out some pretty good references to a couple of the mechanisms of how it might work to reduce mortality in covid-19 patients.

I. How the coronavirus uses Activation of transcription factor NF-kappaB:
1. Targeting Coronaviral Replication and Cellular JAK2 Mediated Dominant NF-κB Activation for Comprehensive and Ultimate Inhibition of Coronaviral Activity

"SARS-CoV-2 uses angiotensin converting enzyme II (ACE2) and transmembrane serine protease 2(TMPRSS2) as cell entry receptors, followed by a cytokine-related syndrome, ARDS, which is induced bythe hyper-activation of the transcription factor NF-kB, most likely in nonimmune cells including lungepithelial cells. ACE2 molecules on the cell surface are occupied by SARS-CoV-2. Angiotensin 2 (AngII)then increases in the serum due to a reduction of ACE2-mediated degradation. SARS-CoV-2 itself activates NF-kB via pattern recognition receptors (PPRs), and the accumulated AngII induces inflammatorycytokines including TNFaand IL-6-soluble (s)IL-6R via disintegrin and metalloprotease 17 (ADAM17),followed by activation of the IL-6 amplifier (IL-6 AMP), which describes enhanced NF-kB activation machinery via the coactivation of NF-kB and transcription factor STAT3. The molecules underlined indicatepossible therapeutic targets for COVID-19, which is a cytokine release syndrome (CRS)"

2.Another key covid mechanism is Phosphorylation of p38 MAPK and its downstream targets in SARS coronavirus-infected cells:

"In the present study, we demonstrated that infection of Vero E6 cells by SARS-CoV induced apoptotic cell death and that p38 MAPK and its downstream targets were phosphorylated during viral replication. Understanding the mechanisms of p38 MAPK activation may lead to successful strategies for targeting these molecules in the therapy of SARS."

II. Evidence for Ivermectin MoA

1.Ivermectin inhibits LPS-induced production of inflammatory cytokines and improves LPS-induced survival in mice:

“Conclusions: The results indicate that ivermectin may inhibit LPS-induced production of inflammatory cytokines by blocking NF-kB pathway and improve LPS-induced survival in mice. This finding might provide a new strategy for the treatment of endotoxemia and associated inflammation.”

2.Avermectin(ivermectin) exerts anti-inflammatory effect by downregulating the nuclear transcription factor kappa-B and mitogen-activated protein kinase activation pathway:

"“We further investigated the effects of the drug on the major signal transduction pathways associated with inflammation: nuclear transcription factor kappa-B (NF-kappaB) and the mitogen-activated protein (MAP) kinases, extracellular signal regulated kinase, p38 and c-Jun N-terminal kinase (JNK). RAW 264.7 cells were pretreated with 0.625, 1.25 or 5 mg/L avermectin 1 h prior to treatment with 1 mg/L LPS. Thirty minutes later, cells were fixed, and NF-kappaB activation was measured by immunocytochemical analysis, or cells were collected and MAP-kinase activation was measured by western blot. Signal transduction studies showed that avermectin significantly inhibits NF-kappaB p65 translocation into the nucleus and inhibits JNK and p38 phosphorylation protein expression. Therefore, avermectin may inhibit LPS-induced production of inflammatory cytokines by blocking NF-kappaB and MAP-kinase in RAW 264.7 cells.”

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