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Characterisation of C101248: A novel selective THIK-1 channel inhibitor for the modulation of microglial NLRP3-inflammasome.
- Source :
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Neuropharmacology [Neuropharmacology] 2023 Feb 15; Vol. 224, pp. 109330. Date of Electronic Publication: 2022 Nov 12. - Publication Year :
- 2023
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Abstract
- Neuroinflammation, specifically the NLRP3 inflammasome cascade, is a common underlying pathological feature of many neurodegenerative diseases. Evidence suggests that NLRP3 activation involves changes in intracellular K <superscript>+</superscript> . Nuclear Enriched Transcript Sort Sequencing (NETSseq), which allows for deep sequencing of purified cell types from human post-mortem brain tissue, demonstrated a highly specific expression of the tandem pore domain halothane-inhibited K <superscript>+</superscript> channel 1 (THIK-1) in microglia compared to other glial and neuronal cell types in the human brain. NETSseq also showed a significant increase of THIK-1 in microglia isolated from cortical regions of brains with Alzheimer's disease (AD) relative to control donors. Herein, we report the discovery and pharmacological characterisation of C101248, the first selective small-molecule inhibitor of THIK-1. C101248 showed a concentration-dependent inhibition of both mouse and human THIK-1 (IC50: ∼50 nM) and was inactive against K2P family members TREK-1 and TWIK-2, and Kv2.1. Whole-cell patch-clamp recordings of microglia from mouse hippocampal slices showed that C101248 potently blocked both tonic and ATP-evoked THIK-1 K <superscript>+</superscript> currents. Notably, C101248 had no effect on other constitutively active resting conductance in slices from THIK-1-depleted mice. In isolated microglia, C101248 prevented NLRP3-dependent release of IL-1β, an effect not seen in THIK-1-depleted microglia. In conclusion, we demonstrated that inhibiting THIK-1 (a microglia specific gene that is upregulated in brains from donors with AD) using a novel selective modulator attenuates the NLRP3-dependent release of IL-1β from microglia, which suggests that this channel may be a potential therapeutic target for the modulation of neuroinflammation in AD.<br />Competing Interests: Declaration of competing interest All authors except for Ali R, SD, CB, Michael H, DB, CM were employers of Cerevance Ltd at the time their contribution to this work. Ali R and CM were supported by Cerevance Ltd for this work. CB, Michael H, and DB have no interest to declare.<br /> (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)
Details
- Language :
- English
- ISSN :
- 1873-7064
- Volume :
- 224
- Database :
- MEDLINE
- Journal :
- Neuropharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 36375694
- Full Text :
- https://doi.org/10.1016/j.neuropharm.2022.109330