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

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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.

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Funding

This research was supported by Korea Drug Development Fund funded by Ministry of Science and ICT, Ministry of Trade, Industry, and Energy, and Ministry of Health and Welfare (HN21C1139, Republic of Korea).

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Author notes

  1. Ji Hun Lee and Sang Hee Ji are contributed equally to this work and share the first authorship.

Authors and Affiliations

  1. Data Convergence Drug Research Center, Therapeutics & Biotechnology Division, Research Institute of Chemical Technology, 141 Gajeong-ro, Yuseong-gu, 34114, Daejeon, Korea

    Ji Hun Lee, Jong Seung Lim, Sunjoo Ahn & Jin Sook Song

  2. Drug Discovery Platform Research Center, Therapeutics & Biotechnology Division, Research Institute of Chemical Technology, 34114, Daejeon, Korea

    Sang Hee Ji & Seong Hwan Kim

  3. Graduate School of New Drug Discovery and Development, Chungnam National University, Daejeon, Korea

    Sang Hee Ji & Seong Hwan Kim

  4. College of Pharmacy, Chungnam National University, Daejeon, Korea

    Ji Hun Lee & Hwi-yeol Yun

  5. New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundataion, 41061, Daegu, Korea

    Ji Hun Lee

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  1. Ji Hun Lee
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Contributions

JHL, SHJ: Investigation, Methodology, Writing-original draft, JSL: Investigation, Methodology, SA, HY: Methodology, Formal analysis, Resources, SHK: Conceptualization, Wiriting-review, Supervision, JSS: Conceptualization, Wiriting-review, Funding acquisition, Supervision.

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Correspondence to Seong Hwan Kim or Jin Sook Song.

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All authors declare that they have no conflicts of interest.

Ethical Approval

All applicable national and institutional guidelines for the care and use of animals were followed. The protocols for animal experiments were approved by the Animal Ethics Committee of Korea Research Institute of Chemical Technology with the code number of 2022-7 F-02-01(approval date: 2022-02-09).

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Lee, J.H., Ji, S.H., Lim, J.S. et al. Anti-neuroinflammatory Effects and Brain Pharmacokinetic Properties of Selonsertib, an Apoptosis signal-regulating Kinase 1 Inhibitor, in mice. Neurochem Res 47, 3829–3837 (2022). https://doi.org/10.1007/s11064-022-03777-9

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