Anti-neuroinflammatory Effects and Brain Pharmacokinetic Properties of Selonsertib, an Apoptosis signal-regulating Kinase 1 Inhibitor, in mice

Selonsertib is a first-in-class apoptosis signal-regulating kinase 1 (ASK1) inhibitor in clinical trials for treating NASH and diabetic kidney disease due to its anti-inflammatory and anti-fibrotic activities. In the present study, we investigated the anti-neuroinflammatory effects and brain pharmacokinetic properties of selonsertib. It inhibited inflammatory cytokines and NO production by suppressing phosphorylated ASK1 in the LPS-stimulated microglial cell line, BV2 cells. Consistent with the in vitro results, selonsertib attenuated plasma and brain TNF-alpha levels in the LPS-induced murine neuroinflammation model. In vitro and in vivo pharmacokinetic studies of selonsertib were conducted in support of central nervous system (CNS) drug discovery. In both Caco-2 and MDR-MDCK cells, selonsertib exhibited a high efflux ratio, showing that it is a P-gp substrate. Selonsertib was rapidly and effectively absorbed into the systemic circulation after oral treatment, with a T-max of 0.5 h and oral bioavailability of 74%. In comparison with high systemic exposure with C-max of 16.2 mu g/ml and AUC of 64 mu g center dot h/mL following oral dosing of 10 mg/kg, the brain disposition of selonsertib was limited, with C-max of 0.08 mu g/g and Kp value of 0.004. This study demonstrates that selonsertib can be a therapeutic agent for neuroinflammatory diseases.

Automated summary

This study investigated the anti-neuroinflammatory effects and brain pharmacokinetic properties of selonsertib. Results showed that selonsertib inhibited inflammatory cytokines and NO production by suppressing ASK1 phosphorylation, and attenuated TNF-alpha levels in a murine neuroinflammation model. Pharmacokinetic studies revealed that selonsertib was rapidly absorbed into the systemic circulation, but had limited brain distribution.