Mitoxantrone, pixantrone, and mitoxantrone (2-hydroxyethyl)piperazine are toll-like receptor 4 antagonists, inhibit NF-κB activation, and decrease TNF-alpha secretion in primary microglia

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Rinne , M K , Mätlik , K , Ahonen , T J , Vedovi , F , Zappia , G , Moreira , V M , Yli-Kauhaluoma , J T , Leino , S , Salminen , O S , Kalso , E A , Airavaara , M T & Xhaard , H G M 2020 , ' Mitoxantrone, pixantrone, and mitoxantrone (2-hydroxyethyl)piperazine are toll-like receptor 4 antagonists, inhibit NF-κB activation, and decrease TNF-alpha secretion in primary microglia ' , European Journal of Pharmaceutical Sciences , vol. 154 , no. 1.11.2020 , 105493 . https://doi.org/10.1016/j.ejps.2020.105493

Title: Mitoxantrone, pixantrone, and mitoxantrone (2-hydroxyethyl)piperazine are toll-like receptor 4 antagonists, inhibit NF-κB activation, and decrease TNF-alpha secretion in primary microglia
Author: Rinne, Maiju Kaarina; Mätlik, Kert; Ahonen, Tiina Johanna; Vedovi, Fabio; Zappia, Giovanni; Moreira, Vânia M.; Yli-Kauhaluoma, Jari Tapani; Leino, Sakari; Salminen, Outi Susanna; Kalso, Eija Anneli; Airavaara, Mikko Tuomas; Xhaard, Henri Guillaume Michel
Contributor: University of Helsinki, Division of Pharmaceutical Chemistry and Technology
University of Helsinki, Department of Pharmacology
University of Helsinki, Division of Pharmaceutical Chemistry and Technology
University of Helsinki, Divisions of Faculty of Pharmacy
University of Helsinki, Pharmaceutical Design and Discovery group
University of Helsinki, Division of Pharmacology and Pharmacotherapy
University of Helsinki, Regenerative pharmacology group
University of Helsinki, HUS Perioperative, Intensive Care and Pain Medicine
University of Helsinki, University Management
University of Helsinki, Staff Services
Date: 2020-11-01
Language: eng
Number of pages: 11
Belongs to series: European Journal of Pharmaceutical Sciences
ISSN: 0928-0987
URI: http://hdl.handle.net/10138/333041
Abstract: Toll-like receptor 4 (TLR4) recognizes various endogenous and microbial ligands and is an essential part in the innate immune system. TLR4 signaling initiates transcription factor NF-κB and production of proinflammatory cytokines. TLR4 contributes to the development or progression of various diseases including stroke, neuropathic pain, multiple sclerosis, rheumatoid arthritis and cancer, and better therapeutics are currently sought for these conditions. In this study, a library of 140 000 compounds was virtually screened and a resulting hit-list of 1000 compounds was tested using a cellular reporter system. The topoisomerase II inhibitor mitoxantrone and its analogues pixantrone and mitoxantrone (2-hydroxyethyl)piperazine were identified as inhibitors of TLR4 and NF-κB activation. Mitoxantrone was shown to bind directly to the TLR4, and pixantrone and mitoxantrone (2- hydroxyethyl)piperazine were shown to inhibit the production of proinflammatory cytokines such as tumor necrosis factor alpha (TNFα) in primary microglia. The inhibitory effect on NF-κB activation or on TNFα pro-duction was not mediated through cytotoxity at ≤ 1 μM concentration for pixantrone and mitoxantrone (2- hydroxyethyl)piperazine treated cells, as assessed by ATP counts. This study thus identifies a new mechanism of action for mitoxantrone, pixantrone, and mitoxantrone (2-hydroxyethyl)piperazine through the TLR4.
Subject: 317 Pharmacy
Mitoxantrone
Pixantrone
Mitoxantrone (2-hydroxyethyl)piperazine
Toll-like receptor 4
Virtual screening
Soft contact lenses
NF-κB
Mitoxantrone
Pixantrone
Mitoxantrone (2-hydroxyethyl)piperazine
Toll-like receptor 4
Virtual screening
NF-kappa B
TOPOISOMERASE-II
INNATE IMMUNITY
SPINAL-CORD
NEUROPATHIC PAIN
STRUCTURAL BASIS
TLR4
RECOGNITION
TAK-242
CELLS
GLIA
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