The NLRP3 Inflammasome: a Prospective Therapeutic Target for Intracerebral Haemorrhage

Abstract

One third of stroke patients will suffer from an intracerebral haemorrhage (ICH) and 40% of these patients will die within 1 month. Most survivors of ICH are left with lifelong disabilities, with no treatments currently available to improve their prognosis. The immune system mounts a prolonged and highly dynamic response to ICH. While this response is vital for haematoma clearance and orchestrating tissue repair mechanisms, the acute phase is predominantly pro-inflammatory and exacerbates brain damage. Dampening this initial inflammatory response has therefore become a major focus for ICH drug development. A crucial aspect of this strategy is the identification of specific, disease-driving immune pathways that can be therapeutically targeted. One such pathway is the NLRP3 inflammasome, a cytosolic protein complex that acts as a key immune cell response to host injury/infection but is also a well-characterised instigator of inflammation-driven brain injury and functional impairment in preclinical ICH models. No NLRP3 inhibitor compounds have been approved for clinical use to date, largely due to safety concerns. To advance therapeutic application of NLRP3 inhibitors for ICH, there is a pressing need to expand and refine both the development of novel NLRP3 inhibitors and the preclinical models used to assess their therapeutic potential. This PhD research addresses these challenges by first validating the NLRP3 inflammasome as a viable therapeutic target to improve functional outcomes after ICH, using a rodent model. Additionally, it identifies and characterizes new NLRP3 inhibitor compounds with potential for further development as therapeutic agents. Lastly, this work characterises the effects of one identified natural product NLRP3 inhibitor in a zebrafish ICH model, laying the foundations for future testing in rodent models. This work in-turn highlights the utility of zebrafish as an innovative, complementary model in preclinical ICH research, offering unique advantages for studying disease pathogenesis and screening potential drug candidates, thereby strengthening the translational pipeline for ICH therapeutics.

Date of Award	2 Jun 2025
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Sally Freeman (Co Supervisor), Catherine Lawrence (Co Supervisor), David Brough (Co Supervisor) & Paul Kasher (Main Supervisor)