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

Neurochem Res. 2022 Dec;47(12):3829-3837. doi: 10.1007/s11064-022-03777-9. Epub 2022 Oct 30.

Abstract

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-α 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 Tmax of 0.5 h and oral bioavailability of 74%. In comparison with high systemic exposure with Cmax of 16.2 µg/ml and AUC of 64 µg·h/mL following oral dosing of 10 mg/kg, the brain disposition of selonsertib was limited, with Cmax of 0.08 µg/g and Kp value of 0.004. This study demonstrates that selonsertib can be a therapeutic agent for neuroinflammatory diseases.

Keywords: Apoptosis signal-regulating kinase 1; Central nervous system; Neuroinflammation; Pharmacokinetics; Selonsertib.

MeSH terms

  • Animals
  • Brain / metabolism
  • Caco-2 Cells
  • Lipopolysaccharides* / pharmacology
  • MAP Kinase Kinase Kinase 5* / metabolism
  • MAP Kinase Kinase Kinase 5* / pharmacology
  • Mice
  • Microglia / metabolism

Substances

  • Lipopolysaccharides
  • MAP Kinase Kinase Kinase 5
  • selonsertib