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

Autor: Ji Hun, Lee, Sang Hee, Ji, Jong Seung, Lim, Sunjoo, Ahn, Hwi-Yeol, Yun, Seong Hwan, Kim, Jin Sook, Song
Rok vydání: 2022
Předmět:
Zdroj: Neurochemical Research. 47:3829-3837
ISSN: 1573-6903
0364-3190
DOI: 10.1007/s11064-022-03777-9
Popis: 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 T
Databáze: OpenAIRE
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