Neuroprotective Effects of the Lithium Salt of a Novel JNK Inhibitor in an Animal Model of Cerebral Ischemia–Reperfusion

dc.contributor.authorSchepetkin, Igor A.
dc.contributor.authorChernysheva, Galina A.
dc.contributor.authorAliev, Oleg I.
dc.contributor.authorKirpotina, Liliya N.
dc.contributor.authorSmol’yakova, Vera I.
dc.contributor.authorOsipenko, Anton N.
dc.contributor.authorPlotnikov, Mark B.
dc.contributor.authorKovrizhina, Anastasia R.
dc.contributor.authorKhlebnikov, Andrei I.
dc.contributor.authorPlotnikov, Evgenii V.
dc.contributor.authorQuinn, Mark T.
dc.date.accessioned2022-12-08T16:43:17Z
dc.date.available2022-12-08T16:43:17Z
dc.date.issued2022-08
dc.description.abstractThe c-Jun N-terminal kinases (JNKs) regulate many physiological processes, including inflammatory responses, morphogenesis, cell proliferation, differentiation, survival, and cell death. Therefore, JNKs represent attractive targets for therapeutic intervention. In an effort to develop improved JNK inhibitors, we synthesized the lithium salt of 11H-indeno[1,2-b]quinoxaline-11-one oxime (IQ-1L) and evaluated its affinity for JNK and biological activity in vitro and in vivo. According to density functional theory (DFT) modeling, the Li+ ion stabilizes the six-membered ring with the 11H-indeno[1,2-b]quinoxaline-11-one (IQ-1) oximate better than Na+. Molecular docking showed that the Z isomer of the IQ-1 oximate should bind JNK1 and JNK3 better than (E)-IQ-1. Indeed, experimental analysis showed that IQ-1L exhibited higher JNK1-3 binding affinity in comparison with IQ-1S. IQ-1L also was a more effective inhibitor of lipopolysaccharide (LPS)-induced nuclear factor-κB/activating protein 1 (NF-κB/AP-1) transcriptional activity in THP-1Blue monocytes and was a potent inhibitor of proinflammatory cytokine production by MonoMac-6 monocytic cells. In addition, IQ-1L inhibited LPS-induced c-Jun phosphorylation in MonoMac-6 cells, directly confirming JNK inhibition. In a rat model of focal cerebral ischemia (FCI), intraperitoneal injections of 12 mg/kg IQ-1L led to significant neuroprotective effects, decreasing total neurological deficit scores by 28, 29, and 32% at 4, 24, and 48 h after FCI, respectively, and reducing infarct size by 52% at 48 h after FCI. The therapeutic efficacy of 12 mg/kg IQ-1L was comparable to that observed with 25 mg/kg of IQ-1S, indicating that complexation with Li+ improved efficacy of this compound. We conclude that IQ-1L is more effective than IQ-1S in treating cerebral ischemia injury and thus represents a promising anti-inflammatory compound.en_US
dc.identifier.citationSchepetkin, I.A.; Chernysheva, G.A.; Aliev, O.I.; Kirpotina, L.N.; Smol’yakova, V.I.; Osipenko, A.N.; Plotnikov, M.B.; Kovrizhina, A.R.; Khlebnikov, A.I.; Plotnikov, E.V.; et al. Neuroprotective Effects of the Lithium Salt of a Novel JNK Inhibitor in an Animal Model of Cerebral Ischemia–Reperfusion. Biomedicines 2022, 10, 2119. https://doi.org/10.3390/ biomedicines10092119en_US
dc.identifier.issn2227-9059
dc.identifier.urihttps://scholarworks.montana.edu/handle/1/17471
dc.language.isoen_USen_US
dc.publisherMDPI AGen_US
dc.rightscc-byen_US
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/en_US
dc.subjectc-Jun N-terminal kinaseen_US
dc.subject11H-indeno[1,2-b]quinoxalin-11-oneen_US
dc.subjectoximeen_US
dc.subjectinterleukin-6en_US
dc.subjectnuclear factor-κBen_US
dc.subjectlithium salten_US
dc.subjectstrokeen_US
dc.titleNeuroprotective Effects of the Lithium Salt of a Novel JNK Inhibitor in an Animal Model of Cerebral Ischemia–Reperfusionen_US
dc.typeArticleen_US
mus.citation.extentfirstpage1en_US
mus.citation.extentlastpage16en_US
mus.citation.issue9en_US
mus.citation.journaltitleBiomedicinesen_US
mus.citation.volume10en_US
mus.data.thumbpage7en_US
mus.identifier.doi10.3390/biomedicines10092119en_US
mus.relation.collegeCollege of Agricultureen_US
mus.relation.departmentMicrobiology & Immunology.en_US
mus.relation.universityMontana State University - Bozemanen_US

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