03435nas a2200577   4500000000100000008004100001260001500042100001700057700001900074700001600093700001400109700001100123700001900134700001500153700001600168700002400184700001800208700001800226700001800244700002000262700002000282700002000302700001700322700002100339700002100360700001900381700002300400700002400423700002100447700002300468700002600491700001900517700001600536700002200552700001500574700001900589700001700608700001800625700002200643700002200665700001600687700001700703700001800720700002200738245011600760856004200876300001400918490000800932520190300940022001402843       2026                            d  c2026-10-011 aJamie Cowley1 aNeale Harrison1 aAshley Pegg1 aHujo Chan1 aZhi Li1 aArshpreet Kaur1 aEmma Welsh1 aAlex Brewin1 aJuan Carlos Yam-Puc1 aGrace Fensome1 aEdward Broome1 aInes M Morano1 aElizabeth Jinks1 aGillian Grafton1 aAlison J Cooper1 aZubair Ahmed1 aAndrew R Stevens1 aFreya G Anderson1 aVictoria Wykes1 aRamesh Chelvarajah1 aGeorgios Tsermoulas1 aIsmail Ughratdar1 aAthanasios Zisakis1 aPhilip J O’Halloran1 aDavid J Davies1 aThomas Land1 aYasir A Chowdhury1 aZenab Sher1 aKamal M Yakoub1 aColin Bergin1 aLuke Galloway1 aRachel Upthegrove1 aCatherine A Brady1 aJohn Gordon1 aOmar Qureshi1 aAntonio Belli1 aNicholas M Barnes00aP2X7 receptor-mediated IL-1β release by human brain tissue: the impact of CNS-penetrant potential therapeutics  uhttps://doi.org/10.1093/brain/awag068  a3614-36300 v1493 aTraumatic brain injury is a major cause of death throughout the world, and currently there are no approved drugs to treat this debilitating condition, emphasizing the clear unmet substantial clinical need. It is well recognized that microglial activation and the hostile neuroinflammatory response arising after the initial insult provide a therapeutic window for pharmacological intervention. The purinergic P2X7 receptor (P2X7R) is a key driver of neuroinflammation in a range of animal models of traumatic brain injury.To generate translational evidence for the role of the P2X7R, we optimized two human inflammatory models, human cells (monocyte-derived microglia) in vitro and human brain tissue ex vivo, to test the impact of clinical-stage brain-penetrant P2X7R antagonists.Using lipopolysaccharide-primed human monocyte-derived microglia, the P2X7R agonist 2′(3′)-O-(4-benzoylbenzoyl) ATP (BzATP), evoked a concentration-dependent increase in pro-inflammatory interleukin (IL)-1β and IL-18 release, which was antagonized in a concentration-dependent manner by selective P2X7R antagonists and also by inhibitors of either the NLRP3 complex or caspase-1, implicating a role for the inflammasome in P2X7R-mediated cytokine release. Using slices of human brain tissue, BzATP similarly evoked cytokine release in a concentration-dependent manner that was also antagonized by selective P2X7R antagonists at pharmacologically relevant concentrations.The present study demonstrates the ability of P2X7R antagonists to suppress the neuroinflammatory response from primed human monocyte-derived microglia and human brain slices to offer direct translational data that central P2X7R antagonism might limit pathology-driven pro-inflammatory responses in the brain. This is predicted to improve the clinical outcomes for patients with traumatic brain injury and other neuroinflammatory pathologies.  a0006-8950