Here are some essential papers, related to the effects of Ivermectin.
The SARS-CoV-2 spike protein binds to bacterial lipopolysaccharide (LPS) and boosts proinflammatory activity (Petruk et al., 2020).
Ivermectin inhibits LPS-induced production of inflammatory cytokines and improves LPS-induced survival in mice (Zhang et al., 2008).
- SEE more on LPS/Endotoxin: posting.php?mode=edit&f=66&p=5938
Bowler JW, Bailey RJ, North RA, Surprenant A - "P2X4, P2Y1 and P2Y2 receptors on rat alveolar macrophages" Br J Pharmacol 140(3):567-75 (2003)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1574050/
3uM - "Ivermectin, a channel modulator that has been shown to enhance specifically P2X4-mediated currents in heterologous expression systems, potentiated ATP-mediated currents in NR8383 cells by up to 20-fold without significantly altering the EC50 value (Figure 2)...The P2Y receptors are most likely P2Y1 and P2Y2 and these couple through phospholipase C to an increase in intracellular calcium and the opening of SK type potassium channels. NOTE: SK type potassium channels are moderated by G-proteins (Tigaret et al., 2018)."
- Tigaret CM, Chamberlain SEL, Sadowski JHLP, Hall J, Ashby MC, Mellor JR - "Convergent Metabotropic Signaling Pathways Inhibit SK Channels to Promote Synaptic Plasticity in the Hippocampus" J Neurosci 38(43):9252-9262 (2018)
https://pubmed.ncbi.nlm.nih.gov/30242046/
viewtopic.php?f=68&t=3089&p=3660#p3660
Chen IS, Kubo Y- "Ivermectin and its target molecules: shared and unique modulation mechanisms of ion channels and receptors by ivermectin" J Physiol 596(10):1833-1845 (2018) doi: 10.1113/JP275236. Epub 2017 Nov 9
https://pubmed.ncbi.nlm.nih.gov/29063617/
"It kills parasites by activating glutamate-gated Cl- channels, and it also targets several ligand-gated ion channels and receptors, including Cys-loop receptors, P2X4 receptors and fernesoid X receptors. Recently, we found that IVM also activates a novel target, the G-protein-gated inwardly rectifying K+ channel, and also identified the structural determinant for the activation."
Chen IS, Tateyama M, Fukata Y, Uesugi M, Kubo Y - "Ivermectin activates GIRK channels in a PIP2 -dependent, Gβγ -independent manner and an amino acid residue at the slide helix governs the activation" J Physiol 595(17):5895-5912 (2017) doi: 10.1113/JP274871
https://pubmed.ncbi.nlm.nih.gov/28715108/
"Electrophysiological recordings in Xenopus oocytes revealed that IVM activates GIRK channel in a phosphatidylinositol-4,5-biphosphate (PIP₂)-dependent manner, and that the IVM-mediated GIRK activation is independent of Gβγ subunits."
NOTE: Gq/11 protein activates PLC, which cleaves phosphatidylinositol 4,5-bisphosphate (PIP₂) into inositol trisphosphate (IP₃) and diacylglycerol (DAG).
Estrada-Mondragon A, Lynch JW - "Functional characterization of ivermectin binding sites in α1β2γ2L GABA(A) receptors" Front Mol Neurosci 8:55. doi: 10.3389/fnmol.2015.00055 (2015)
https://www.frontiersin.org/articles/10 ... 00055/full
Hashimoto H, Sudo T, Maruta H, Nishimura R - "The direct PAK1 inhibitor, TAT-PAK18, blocks preferentially the growth of human ovarian cancer cell lines in which PAK1 is abnormally activated by autophosphorylation at Thr 423" Drug Discov Ther 4(1):1-4 (2010) PMID: 22491145.
https://www.ddtjournal.com/article/283
"αGluClRs are typically activated by low (< 20) 75 nanomolar concentrations [2,14,18,19], whereas GABAARs and GlyRs require concentrations in the low (1-10) micromolar range [20-23]. HisCls and pHCls respond to micromolar ivermectin, but the dose dependency has not been established [24-26]. At several other receptors, ivermectin activates no current but modulates (inhibits or potentiates) the responses to the neurotransmitter agonist. These include some invertebrate GABAARs and the human α7 nAChR (below)." (Lynagh & Lynch, 2012)
Ito M, Matsuoka I - "Regulation of purinergic signaling by prostaglandin E2 in murine macrophages" J Pharmacol Sci 107(4):443-50 (2008)
https://pubmed.ncbi.nlm.nih.gov/18678987/
"Furthermore, ivermectin, an activator of the P2X4-receptor channel, enhanced the ATP-induced [Ca2+]i elevation." (Gq/11 regulate calcium mobilization)
Jiang L, Wang P, Sun YJ, Wu YJ - "Ivermectin reverses the drug resistance in cancer cells through EGFR/ERK/Akt/NF-κB pathway" J Exp Clin Cancer Res 38(1):265 (2019)
https://pubmed.ncbi.nlm.nih.gov/31215501/
"Our results indicated that ivermectin at its very low dose, which did not induce obvious cytotoxicity, drastically reversed the resistance of the tumor cells to the chemotherapeutic drugs both in vitro and in vivo. Mechanistically, ivermectin reversed the resistance mainly by reducing the expression of P-glycoprotein (P-gp) via inhibiting the epidermal growth factor receptor (EGFR), not by directly inhibiting P-gp activity. Ivermectin bound with the extracellular domain of EGFR, which inhibited the activation of EGFR and its downstream signaling cascade ERK/Akt/NF-κB. The inhibition of the transcriptional factor NF-κB led to the reduced P-gp transcription."
Khakh BS, Proctor WR, Dunwiddie TV, Labarca C, Lester HA - "Allosteric control of gating and kinetics at P2X(4) receptor channels" J Neurosci 19(17):7289-99 (1999). doi: 10.1523/JNEUROSCI.19-17-07289.1999.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6782529/
Layhadi JA, Fountain SJ - "P2X4 Receptor-Dependent Ca2+ Influx in Model Human Monocytes and Macrophages" Int J Mol Sci 18(11):2261 (2017)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5713231/
(Gq/11)
Lee JY, Lim W, Ham J, Kim J, You S, Song G - "Ivermectin induces apoptosis of porcine trophectoderm and uterine luminal epithelial cells through loss of mitochondrial membrane potential, mitochondrial calcium ion overload, and reactive oxygen species generation" Pestic Biochem Physiol 159:144-153 (2019) doi: 10.1016/j.pestbp.2019.06.009
https://pubmed.ncbi.nlm.nih.gov/31400776/
Lynagh T, Lynch JW - "Ivermectin binding sites in human and invertebrate Cys-loop receptors" Trends Pharmacol Sci 33(8):432-41 (2012) doi: 10.1016/j.tips.2012.05.002. Epub 2012 Jun 5. PMID: 22677714.
https://core.ac.uk/reader/15149400?utm_source=linkout
Nagaoka M, Nara M, Tamada T, Kume H, Oguma T, Kikuchi T, Zaini J, Moriya T, Ichinose M, Tamura G, Hattori T - "Regulation of adenosine 5'-triphosphate (ATP)-gated P2X(4) receptors on tracheal smooth muscle cells" Respir Physiol Neurobiol 166(1):61-7 (2009). doi: 10.1016/j.resp.2009.02.002
https://pubmed.ncbi.nlm.nih.gov/19429520/
"We examined the effects of extracellular adenosine 5'-triphosphate (ATP) on single airway smooth muscle (ASM) cells from porcine trachea using a patch-clamp technique. ATP induced a sustained inward current. Phospholipase C inhibitor U-73122 failed to inhibit the current, suggesting the involvement of P2X receptor. A specific effecter of P2X(4), ivermectin, augmented the current indicating the existence of P2X(4) receptors."
Petruk G, Puthia M, Petrlova J, Samsudin F, Strömdahl AC, Cerps S, Uller L, Kjellström S, Bond PJ, Schmidtchen AA - "SARS-CoV-2 spike protein binds to bacterial lipopolysaccharide and boosts proinflammatory activity" J Mol Cell Biol 12(12):916-932 (2020). doi: 10.1093/jmcb/mjaa067. PMID: 33295606; PMCID: PMC7799037.
https://academic.oup.com/jmcb/article/12/12/916/6028992
Seil M, Fontanils U, Etxebarria IG, Pochet S, Garcia-Marcos M, Marino A, Dehaye JP - "Pharmacological evidence for the stimulation of NADPH oxidase by P2X(7) receptors in mouse submandibular glands" Purinergic Signal 4(4):347-55 (2008). doi: 10.1007/s11302-008-9118-y
https://pubmed.ncbi.nlm.nih.gov/18581262/
From these results it is concluded that the activation of the P2X(7) receptors from submandibular glands triggers an intracellular signalling cascade involving protein kinase C and MAP kinase leading to the stimulation of NADPH oxidase and the subsequent generation of reactive oxygen species.
Sophocleous RA, Miles NA, Ooi L, Sluyter R - "P2Y2 and P2X4 Receptors Mediate Ca2+ Mobilization in DH82 Canine Macrophage Cells" Int J Mol Sci. 21(22):8572 (2020)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7696671/
Hq/11 - "Purinergic receptors of the P2 subclass are commonly found in human and rodent macrophages where they can be activated by adenosine 5'-triphosphate (ATP) or uridine 5'-triphosphate (UTP) to mediate Ca2+ mobilization, resulting in downstream signalling to promote inflammation and pain...ATP-induced responses were only partially inhibited by the P2X4 receptor antagonists, 2',3'-O-(2,4,6-trinitrophenyl)-ATP (TNP-ATP), paroxetine and 5-BDBD, but were strongly potentiated by ivermectin...P2Y2 receptor-mediated Ca2+ mobilization was inhibited by U-73122 and 2-aminoethoxydiphenyl borate (2-APB), indicating P2Y2 receptor coupling to the phospholipase C and inositol triphosphate signal transduction pathway."
Stokes L - "Rab5 regulates internalization of P2X4 receptors and potentiation by Ivermectin" Purinergic Signal 9(1):113-21 (2013) doi: 10.1007/s11302-012-9336-1
https://pubmed.ncbi.nlm.nih.gov/23086000/
Wang B, Murakami Y, Ono M, Fujikawa S, Matsuyama H, Unno T, Naitou K, Tanahashi Y - "Muscarinic suppression of ATP-sensitive K+ channels mediated by the M3/Gq/11/phospholipase C pathway contributes to mouse ileal smooth muscle contractions" Am J Physiol Gastrointest Liver Physiol. 315(4):G618-G630 (2018)
https://pubmed.ncbi.nlm.nih.gov/30001145/
"M3 receptors inhibit the activity of these channels via a Gq/11/PLC-dependent but PKC-independent pathways, thereby contributing to membrane depolarization and contraction of smooth muscles. NEW & NOTEWORTHY We systematically investigated the regulation of ATP-sensitive K+ channels by muscarinic receptors expressed on mouse ileal smooth muscles. We found that M3 receptors inhibit the activity of ATP-sensitive K+ channels via a Gq/11/PLC-dependent, but PKC-independent, pathway."
Zhang PP, Zhang G, Zhou W, Weng SJ, Yang XL, Zhong YM - "Signaling mechanism for modulation by ATP of glycine receptors on rat retinal ganglion cells" Sci Rep 6:28938 (2016)
"The ATP effect was abolished by intracellular dialysis of a Gq/11 protein inhibitor and phosphatidylinositol (PI)-phospholipase C (PLC) inhibitor, but not phosphatidylcholine (PC)-PLC inhibitor. The ATP effect was accompanied by an increase in [Ca(2+)]i through the IP3-sensitive pathway and was blocked by intracellular Ca(2+)-free solution. Furthermore, the ATP effect was eliminated in the presence of PKC inhibitors. Neither PKA nor PKG system was involved. These results suggest that the ATP-induced suppression may be mediated by a distinct Gq/11/PI-PLC/IP3/Ca(2+)/PKC signaling pathway, following the activation of P2Y1,11 and other P2Y subtypes. Consistently, ATP suppressed glycine receptor-mediated light-evoked inhibitory postsynaptic currents of OFF-GCs. These results suggest that ATP may modify the ON-to-OFF crossover inhibition, thus changing action potential patterns of OFF-GCs."
Zhang X, Li J, Chen C, Ci X, Yu Q, Zhang X, Deng X - "Protective effect of abamectin on acute lung injury induced by lipopolysaccharide in mice"
Fundam Clin Pharmacol 25(6):700-7 (2011) doi: 10.1111/j.1472-8206.2010.00896.x.
https://pubmed.ncbi.nlm.nih.gov/21118302/
Abamectin, a broad-spectrum antiparasitic agent, has been shown to exert an anti-inflammatory effect, in vitro, by down regulating both the nuclear transcription factor kappa-B and the mitogen-activated protein kinase (MAPK) activation pathway...Furthermore, p38MAPK, ERK, and IκB were activated in 10 h after LPS treatment, which could be blunted by Abamectin. These results indicate that abamectin could attenuate inflammatory injury induced by LPS through MAPK and NF-κB passway.
Zhang X, Song Y, Xiong H, Ci X, Li H, Yu L, Zhang L, Deng X - "Inhibitory effects of ivermectin on nitric oxide and prostaglandin E2 production in LPS-stimulated RAW 264.7 macrophages" Int Immunopharmacol 9(3):354-9 (2009)
https://pubmed.ncbi.nlm.nih.gov/19168156/
"...the phosphorylation of p38, ERK1/2, and JNK in LPS-stimulated RAW 264.7 cells was suppressed by ivermectin in a dose-dependent manner. These results suggest that ivermectin suppresses NO and PGE(2) production, as well as iNOS and COX-2 expression, by inhibiting phosphorylation of mitogen-activated protein kinases (MAPK) (p38, ERK1/2, and JNK) in LPS-stimulated RAW 264.7 cells."
Zhu T, Liu X, Song J, Li D, Pang XJ, Wang SH, Li QR, Fu DJ, Zhang SY, Xie HZ - "Ras/Raf/MEK/ERK pathway axis mediated neurotoxicity induced by high-risk pesticide residue-Avermectin" Environ Toxicol 36(5):984-993 (2021)
https://pubmed.ncbi.nlm.nih.gov/33381906/
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See also:
Review of pharmacokinetics
https://www.ncbi.nlm.nih.gov/pmc/articl ... -01169.pdf
Hussman JP - "Cellular and Molecular Pathways of COVID-19 and Potential Points of Therapeutic Intervention" Front Pharmacol 11:1169 (2020)
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Ivermectin & Thyroid
Bäck CM, Stohr S, Schäfer EA, Biebermann H, Boekhoff I, Breit A, Gudermann T, Büch TR - "TSH induces metallothionein 1 in thyrocytes via Gq/11- and PKC-dependent signaling" J Mol Endocrinol 51(1):79-90 (2013)
https://pubmed.ncbi.nlm.nih.gov/23613280/
Westergard T, Salari R, Martin JV, Brannigan G - "Interactions of L-3,5,3'-Triiodothyronine [corrected], Allopregnanolone, and Ivermectin with the GABAA Receptor: Evidence for Overlapping Intersubunit Binding Modes" PLoS One 10(9):e0139072 (2015)
https://pubmed.ncbi.nlm.nih.gov/26421724/
"Activation of the GABAA receptor by IVM [ivermectin] was inhibited by the presence of T3 (Fig 3A) with a representative tracing shown for 10 μM T3 (Fig 3A inset). Further representative traces are in supplementary information (S2 Fig). For the maximal concentrations of T3 used in this study (about 50 μM), response to IVM was reduced to 51% ± 5% of control, with an IC50 for T3 of 7 ± 3 μM (Fig 3A); non-vanishing IVM response at 20 μM T3 likely corresponds to the onset of the high concentration regime associated with positive modulation..." (Westergard et al., 2015)
Ivermectin effects on calcium are well documented.
Park H, Song G, Lim W - "Ivermectin-induced programmed cell death and disruption of mitochondrial membrane potential in bovine mammary gland epithelial cells" Pestic Biochem Physiol 163:84-93 (2020) doi: 10.1016/j.pestbp.2019.10.011
https://pubmed.ncbi.nlm.nih.gov/31973874/
Lee JY, Lim W, Ham J, Kim J, You S, Song G - "Ivermectin induces apoptosis of porcine trophectoderm and uterine luminal epithelial cells through loss of mitochondrial membrane potential, mitochondrial calcium ion overload, and reactive oxygen species generation" Pestic Biochem Physiol 159:144-153 (2019) doi: 10.1016/j.pestbp.2019.06.009
https://pubmed.ncbi.nlm.nih.gov/31400776/
Gq/11
Bernier LP, Ase AR, Boué-Grabot É, Séguéla P - "Inhibition of P2X4 function by P2Y6 UDP receptors in microglia" Glia 61(12):2038-49 (2013) doi: 10.1002/glia.22574
https://pubmed.ncbi.nlm.nih.gov/24123515/
"ATP receptors in the central nervous system (CNS) are divided into 2 major classes, ionotropic (P2Xn) and G protein-coupled (P2Yn) ATP receptors. P2Xn receptors, a member of the 2-transmembrane family, contain non-selective cation channels that may play a role in rapid synaptic transmission. Seven subtypes of P2Xn were reported so far. Although all of these subtypes are distributed in the CNS, P2X4 and P2X6 are most abundantly and widely distributed. P2X3 is distributed only in trigeminal ganglia neurons as well as in small-diameter DRG neurons, suggesting their relation to pain. P2Yn receptors, a member of the 7-transmembrane superfamily, are coupled with Gq/11 to activate PLC beta. These receptors are thought to play an important role in the modulation of synaptic efficacy. Seven subtypes of P2Yn were reported so far. P2Y1, P2Y2, P2Y3 and P2Y4 are distributed in the CNS. Neither selective agonists nor antagonists to P2Xn and P2Yn are known." (Inoue, 1997)
- Inoue K - "ATP receptors in the central nervous system" Nihon Yakurigaku Zasshi 110(4):173-82 (1997) Japanese. doi: 10.1254/fpj.110.173
https://pubmed.ncbi.nlm.nih.gov/9396022/
https://onlinelibrary.wiley.com/doi/10.1002/glia.20118
"The astrocytic protection by the P2Y1 receptor agonist 2-methylthio-ADP was inhibited by an intracellular Ca2 chelator and a blocker of phospholipase C, indicating the involvement of intracellular signals mediated by Gq/11- coupled P2Y1 receptors...The ATP-induced protection was inhibited by cycloheximide, a protein synthesis inhibitor, and it took more than 12 h for the onset of the protective action.Taken together, ATP acts on P2Y1 receptors coupled to Gq/11, resulting in the upregulation of oxidoreductase genes, leading to the protection of astrocytes against H2O2."