The direct NLRP3 inhibitor and Phase 3 small molecule anticancer agent, RRx‐001, protects aged triple transgenic Alzheimer’s disease model mice from CNS degeneration and cognitive decline

Background RRx‐001 is an aerospace‐derived, intravenously administered NLRP3‐specific inhibitor with confirmed CNS‐penetrant properties and a favorable safety profile in a Phase 3 clinical trial. It is under investigation as an anticancer agent, a chemoradioprotector for oral mucositis and a prophylactic for acute graft vs. host disease (aGVHD). RRx‐001 has been shown to reduce interleukin‐1β (IL‐1β) production in vivo and to attenuate the severity both of experimental autoimmune encephalomyelitis (EAE), a disease model of multiple sclerosis, and dextran sulfate sodium (DSS)‐induced colitis. Method In the present study, the neuroprotective effects of 2mg/kg RRx‐001 administration on Alzheimer’s Disease (AD), which has been linked to aberrant NLRP3 activation, were evaluated via i.p. injection once weekly for 3 months on aged (21‐24 months old) triple transgenic AD model (3xTg‐AD) mice and control non‐transgenic (NonTg) mice. Result This sub‐chronic administration of RRx‐001 improved performance on learning and spatial memory tasks and greater risk assessment behavior based on the elevated plus maze test. A significant increase in reduced glutathione and a decrease in lipid peroxidation and amyloid plaque density were also observed in the 3xTg‐AD mice. Conclusion Together, these findings suggest that RRx‐001 reverses histological hallmarks of AD and protects cognitive and emotional function in aged 3xTg‐AD mice