Ivermectin

Introduction

Andy Crump of Kitasato University, Minato-Ku, Japan has a good introduction to ivernectin that includes Satoshi Ōmura discovering this compound in the soil bacterium Streptomyces avermectinius. Many in North America now ivernectin as a drug to prevent heart worms in dogs. Dr Crump points to glutamate-gated chloride channels in invertebrates as well as GABA-, histamine- and pH-sensitive chloride channels.[1] The mammalian P2X4 ATP receptor was also mentioned.

A review out of nstituto Nacional de Cancerología, México explores the use of Ivernectin as a cancer drug. These authors mentioned several protein targets. The third column was their references. PubMed was searched for backup that had something to do with lysosomes and authophagy.

Target	Effect	comments
MDR protein	Inhibition	preventing export of chemotherapy drugs
Chloride channel	Increase of activity	opening of plasma membrane Cl- channels, ROS generation, loss of mitochondria membrane potential [3]
Akt/mTOR pathway	Inhibition	Mitochondria damage and AMP kinase are part of this mTOR pathway. [4]
P2X7/P2X7 receptors	Activation	ATP purinergic receptors, p2x4 is in lysosome. Opened by lysomal ATP and increase luminal pH [5] Activation of P2X7 is verymuch involve in inducing mitophagy. [9]
PAK1 protein	Inhibition	p21 activated protein kinase 1 levels were decreased leading to increased autophagy.[6]
WNT-TCF pathway	Inhibition	Wnt contributes to coat color but could not explain differences in coat color in CIC7 dysfunctional mice. [7]
SIN3 domain	Inhibition	Sin3 a transcription adaptor, straying from Juarez review, SIN3 may have some role in autophagy [8]
NS3 DDX23 helicase	Inhibition	unwind DNA prior to transcription
Nanog/Sox2/Oct4 genes	Downregulation	This one was a dead end.

Other companies are selling compounds targeting mTOR and the lysosomes. This company doesn’t have much to say what is in it except deer antlers, an ingredient in traditional Chinese medicine.

Ivermectin target P2X7 in microglia inflammation[9]

Note that these authors did not use Ivernectin. They used the channel’s normal agonist ATP and a a specific analog BrATP. P2X is a family of purine gated cacium channels.

In order to link the energy-sensing kinase AMPK and P2X7 signaling, the authors first determined the effects of two P2X7 agonists, ATP and BzATP, on AMPK activation. In BV-2 microglia, they found a time-dependent and rapid AMPK phosphorylation upon agonist treatment. A438079, the P2X7 competitive antagonist. Note that in their summary cratoon AMPK is inhibiting mTOR. AMPK is activated by calcium calmodulin kinase (a sensor of Ca2+) and of the ADP/ATP and AMP/ATP levels.

Points from the Sekur discussion [9]

• AMPK is an important controller of mitophagy, mitochondrial dynamics, and biogenesis.
• AMPK id impotysny in initiation of the autophagic flux via . With regard to mitophagy, AMPK is a key signaling molecule to initiate autophagic flux via PINK (a mitochondrial kinase) and Parkin (an ubiquitin ligase) that are very much part of mitophag.
• AMPK to phosphorylate PINK1 at S495, leading to mitophagy.
• P2X7 activation can increase PINK and Parkin in microglia cells. In terms of mitochondrial dynamics,
• AMPK inhibits Drp-1, a cytoplasmic guanosine triphosphatase and catalyzes mitochondrial fission.
• AMPK phosphorylates MFF, a mitochondrial outer-membrane receptor for Drp1.

References

1. Crump, A. Ivermectin: enigmatic multifaceted ‘wonder’ drug continues to surprise and exceed expectations. J Antibiot 70, 495–505 (2017). free article
2. Juarez M, Schcolnik-Cabrera A, Dueñas-Gonzalez A. The multitargeted drug ivermectin: from an antiparasitic agent to a repositioned cancer drug. Am J Cancer Res. 2018 Feb 1;8(2):317-331. PMC free article
3. Wood TE, Ward R, Minden MD, Batey RA, Datti A, Wrana J, Kelley SO, Schimmer AD. The antiparasitic agent ivermectin induces chloride-dependent membrane hyperpolarization and cell death in leukemia cells. Blood. 2010 Nov 4;116(18):3593-603. free article
4. Wang X, Wang J, Zhang P, Zhang C, Wang W, Wu M, Xu W, Tao L, Li Z, Zhang Y. Cytotoxicity and Autophagy Induced by Ivermectin via AMPK/mTOR Signaling Pathway in RAW264.7 Cells. Molecules. 2023 Feb 27;28(5):2201 PMC free article
5. Huang P, Zou Y, Zhong XZ, Cao Q, Zhao K, Zhu MX, Murrell-Lagnado R, Dong XP. P2X4 forms functional ATP-activated cation channels on lysosomal membranes regulated by luminal pH. J Biol Chem. 2014 Jun 20;289(25):17658-67. PMC free article
6. Dou Q, Chen HN, Wang K, Yuan K, Lei Y, Li K, Lan J, Chen Y, Huang Z, Xie N, Zhang L, Xiang R, Nice EC, Wei Y, Huang C. Ivermectin induces cytostatic autophagy by blocking the PAK1/Akt axis in breast cancer. Cancer Res. 2016;76:4457–69. [PubMed]
7. Weinert S, Jabs S, Hohensee S, Chan WL, Kornak U, Jentsch TJ. Transport activity and presence of ClC-7/Ostm1 complex account for different cellular functions. EMBO Rep. 2014 Jul;15(7):784-91. PMC free article
8. Sharma M, Pandey R, Saluja D. ROS is the major player in regulating altered autophagy and lifespan in sin-3 mutants of C. elegans. Autophagy. 2018;14(7):1239-1255. PMC free article
9. Sekar P, Huang DY, Hsieh SL, Chang SF, Lin WW. AMPK-dependent and independent actions of P2X7 in regulation of mitochondrial and lysosomal functions in microglia. Cell Commun Signal. 2018 Nov 20;16(1):83. PMC free article