Pre-symptomatic Caspase-1 inhibitor delays cognitive decline in a mouse model of Alzheimer disease and aging

VX-765 pre-symptomatic treatment delays cognitive deficits

To determine if sufficient VX-765 reaches the brain after intraperitoneal (IP) injections at 50 mg • kg⁻¹, VX-765 and VRT-043198 concentrations were measured by LC-MS/MS in the plasma, whole brain, and cerebrospinal fluid (CSF) at 0.25, 0.5, 1, 3, 6, 8 and 24 h after a single intraperitoneal injection (Fig. 1). VX-765 and VRT-043198 reached plasma concentrations 100- and 20,000-fold (Table 1 and Fig. 1a), brain concentrations 50- and 170-fold (Table 2 and Fig. 1b), and CSF concentrations 100- and 4000-fold (Table 3 and Fig. 1c) their respective in vitro Casp1 IC₅₀¹⁹ within 0.25 h post-injection. VRT-043198 levels surpassed VX-765 concentrations, which indicates the rapid conversion of the prodrug, VX-765, into VRT-043198 in all three compartments. The t_1/2 half-life of VX-765 was 3.2 h in plasma (Table