Characterisation of C101248: A novel selective THIK-1 channel inhibitor for the modulation of microglial NLRP3-inflammasome

• DOI: 10.1016/j.neuropharm.2022.109330
• Publication Date: 2022-11-12T03:08:59Z
• Authors: Bernardino Ossola; Ali Rifat; Anna Rowland; Helen Hunter; Samuel Drinkall; Clare Bender; Mayida Hamlischer; Martin Teall; Russell Burley; Daneil F. Barker; David Cadwalladr; Louise Dickson; Jason M.K. Lawrence; Jenna R.M. Harvey; Marina Lizio; Xiao Xu; Edel Kavanagh; Toni Cheung; Steve Sheardown; Catherine B. Lawr...; Michael Harte; David Brough; Christian Madry; Kim Matthews; Kevin Doyle; Keith Page; Justin Powell; Nicola L. Brice; Roland W. Bürli; Mark B. Carlton; Lee A. Dawson
• Keywords: 0303 health sciences; Inflammasomes; Brain; Article; 3. Good health; Mice; 03 medical and health sciences; Potassium Channels, Tandem Pore Domain; Alzheimer Disease; Neuroinflammatory Diseases; NLR Family, Pyrin Domain-Containing 3 Protein; Animals; Humans; Microglia

Neuroinflammation, specifically the NLRP3 inflammasome cascade, is a common underlying pathological feature of many neurodegenerative diseases. Evidence suggests that activation involves changes in intracellular K+. Nuclear Enriched Transcript Sort Sequencing (NETSseq), which allows for deep sequencing purified cell types from human post-mortem brain tissue, demonstrated highly specific expression tandem pore domain halothane-inhibited K+ channel 1 (THIK-1) microglia compared to other glial and neuronal brain. NETSseq also showed significant increase THIK-1 isolated cortical regions brains with Alzheimer's disease (AD) relative control donors. Herein, we report discovery pharmacological characterisation C101248, first selective small-molecule inhibitor THIK-1. C101248 concentration-dependent inhibition both mouse (IC50: ∼50 nM) was inactive against K2P family members TREK-1 TWIK-2, Kv2.1. Whole-cell patch-clamp recordings hippocampal slices potently blocked tonic ATP-evoked currents. Notably, had no effect on constitutively active resting conductance THIK-1-depleted mice. In microglia, prevented NLRP3-dependent release IL-1β, an not seen microglia. conclusion, inhibiting (a gene upregulated donors AD) using novel modulator attenuates IL-1β this may be potential therapeutic target modulation neuroinflammation AD.