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dc.contributor.authorSchepetkin (Shchepyotkin), Igor Aleksandrovichen
dc.contributor.authorShernysheva, Galina Anatoljevnaen
dc.contributor.authorAliev, Oleg Ibragimovichen
dc.contributor.authorKirpotina, Liliya Nikolaevnaen
dc.contributor.authorSmol’iakova, Vera Ivanovnaen
dc.contributor.authorOsipenko, Anton Nikolaevichen
dc.contributor.authorPlotnikov, Mark Borisovichen
dc.contributor.authorKovrizhina, Anastasia Ruslanovnaen
dc.contributor.authorKhlebnikov, Andrey Ivanovichen
dc.contributor.authorPlotnikov, Evgeny Vladimirovichen
dc.contributor.authorQuinn, Marken
dc.date.accessioned2023-03-31T07:12:58Z-
dc.date.available2023-03-31T07:12:58Z-
dc.date.issued2022-
dc.identifier.citationNeuroprotective Effects of the Lithium Salt of a Novel JNK Inhibitor in an Animal Model of Cerebral Ischemia-Reperfusion / I. A. Schepetkin (Shchepyotkin), G. A. Shernysheva, O. I. Aliev [et al.] // Biomedicines. — 2022. — Vol. 10, iss. 9. — [2119, 16 p.].en
dc.identifier.urihttp://earchive.tpu.ru/handle/11683/74930-
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
dc.format.mimetypeapplication/pdf-
dc.language.isoenen
dc.publisherMDPI AGen
dc.relation.ispartofBiomedicines. 2022. Vol. 10, iss. 9en
dc.rightsinfo:eu-repo/semantics/openAccess-
dc.rightsAttribution-NonCommercial 4.0 Internationalen
dc.rights.urihttps://creativecommons.org/licenses/by-nc/4.0/-
dc.sourceBiomedicinesen
dc.subjectоксимыru
dc.subjectинтерлейкиныru
dc.subjectc-Jun N-terminal kinaseen
dc.subject11H-indeno[1,2-b]quinoxalin-11-oneen
dc.subjectoximeen
dc.subjectinterleukin-6en
dc.subjectnuclear factor-κBen
dc.subjectlithium salten
dc.subjectstrokeen
dc.titleNeuroprotective Effects of the Lithium Salt of a Novel JNK Inhibitor in an Animal Model of Cerebral Ischemia-Reperfusionen
dc.typeArticleen
dc.typeinfo:eu-repo/semantics/article-
dc.typeinfo:eu-repo/semantics/publishedVersion-
dcterms.audienceResearchesen
local.description.firstpage2119-
local.filepathreprint-nw-39916.pdf-
local.filepathhttps://doi.org/10.3390/biomedicines10092119-
local.identifier.bibrecRU\TPU\network\39916-
local.identifier.perskeyRU\TPU\pers\37358-
local.identifier.perskeyRU\TPU\pers\46608-
local.identifier.perskeyRU\TPU\pers\33927-
local.identifier.perskeyRU\TPU\pers\32469-
local.issue9-
local.localtypeСтатьяru
local.volume10-
dc.identifier.doi10.3390/biomedicines10092119-
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