Neuroprotective Effects of the Lithium Salt of a Novel JNK Inhibitor in an Animal Model of Cerebral Ischemia–Reperfusion
The c-Jun <i>N</i>-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 dev...
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MDPI AG
2022-08-01
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| author | Igor A. Schepetkin Galina A. Chernysheva Oleg I. Aliev Liliya N. Kirpotina Vera I. Smol’yakova Anton N. Osipenko Mark B. Plotnikov Anastasia R. Kovrizhina Andrei I. Khlebnikov Evgenii V. Plotnikov Mark T. Quinn |
| author_facet | Igor A. Schepetkin Galina A. Chernysheva Oleg I. Aliev Liliya N. Kirpotina Vera I. Smol’yakova Anton N. Osipenko Mark B. Plotnikov Anastasia R. Kovrizhina Andrei I. Khlebnikov Evgenii V. Plotnikov Mark T. Quinn |
| author_sort | Igor A. Schepetkin |
| collection | DOAJ |
| description | The c-Jun <i>N</i>-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 11<i>H</i>-indeno[1,2-<i>b</i>]quinoxaline-11-one oxime (<b>IQ-1L</b>) and evaluated its affinity for JNK and biological activity in vitro and in vivo. According to density functional theory (DFT) modeling, the Li<sup>+</sup> ion stabilizes the six-membered ring with the 11<i>H</i>-indeno[1,2-<i>b</i>]quinoxaline-11-one (<b>IQ-1</b>) oximate better than Na<sup>+</sup>. Molecular docking showed that the <i>Z</i> isomer of the <b>IQ-1</b> oximate should bind JNK1 and JNK3 better than (<i>E</i>)-<b>IQ-1</b>. Indeed, experimental analysis showed that <b>IQ-1L</b> exhibited higher JNK1-3 binding affinity in comparison with <b>IQ-1S</b>. <b>IQ-1L</b> 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, <b>IQ-1L</b> 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 <b>IQ-1L</b> 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 <b>IQ-1L</b> was comparable to that observed with 25 mg/kg of <b>IQ-1S,</b> indicating that complexation with Li<sup>+</sup> improved efficacy of this compound. We conclude that <b>IQ-1L</b> is more effective than <b>IQ-1S</b> in treating cerebral ischemia injury and thus represents a promising anti-inflammatory compound. |
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| spelling | doaj.art-954dadc088984656bafaaa8b1ac9138c2023-11-23T15:09:28ZengMDPI AGBiomedicines2227-90592022-08-01109211910.3390/biomedicines10092119Neuroprotective Effects of the Lithium Salt of a Novel JNK Inhibitor in an Animal Model of Cerebral Ischemia–ReperfusionIgor A. Schepetkin0Galina A. Chernysheva1Oleg I. Aliev2Liliya N. Kirpotina3Vera I. Smol’yakova4Anton N. Osipenko5Mark B. Plotnikov6Anastasia R. Kovrizhina7Andrei I. Khlebnikov8Evgenii V. Plotnikov9Mark T. Quinn10Department of Microbiology and Cell Biology, Montana State University, Bozeman, MT 59717, USADepartment of Pharmacology, Goldberg Research Institute of Pharmacology and Regenerative Medicine, Tomsk NRMC, 634028 Tomsk, RussiaDepartment of Pharmacology, Goldberg Research Institute of Pharmacology and Regenerative Medicine, Tomsk NRMC, 634028 Tomsk, RussiaDepartment of Microbiology and Cell Biology, Montana State University, Bozeman, MT 59717, USADepartment of Pharmacology, Goldberg Research Institute of Pharmacology and Regenerative Medicine, Tomsk NRMC, 634028 Tomsk, RussiaDepartment of Pharmacology, Siberian State Medical University, 2 Moskovskiy tract, 634050 Tomsk, RussiaDepartment of Pharmacology, Goldberg Research Institute of Pharmacology and Regenerative Medicine, Tomsk NRMC, 634028 Tomsk, RussiaKizhner Research Center, Tomsk Polytechnic University, 634050 Tomsk, RussiaKizhner Research Center, Tomsk Polytechnic University, 634050 Tomsk, RussiaResearch School of Chemistry and Applied Biomedical Sciences, Tomsk Polytechnic University, 634050 Tomsk, RussiaDepartment of Microbiology and Cell Biology, Montana State University, Bozeman, MT 59717, USAThe c-Jun <i>N</i>-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 11<i>H</i>-indeno[1,2-<i>b</i>]quinoxaline-11-one oxime (<b>IQ-1L</b>) and evaluated its affinity for JNK and biological activity in vitro and in vivo. According to density functional theory (DFT) modeling, the Li<sup>+</sup> ion stabilizes the six-membered ring with the 11<i>H</i>-indeno[1,2-<i>b</i>]quinoxaline-11-one (<b>IQ-1</b>) oximate better than Na<sup>+</sup>. Molecular docking showed that the <i>Z</i> isomer of the <b>IQ-1</b> oximate should bind JNK1 and JNK3 better than (<i>E</i>)-<b>IQ-1</b>. Indeed, experimental analysis showed that <b>IQ-1L</b> exhibited higher JNK1-3 binding affinity in comparison with <b>IQ-1S</b>. <b>IQ-1L</b> 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, <b>IQ-1L</b> 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 <b>IQ-1L</b> 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 <b>IQ-1L</b> was comparable to that observed with 25 mg/kg of <b>IQ-1S,</b> indicating that complexation with Li<sup>+</sup> improved efficacy of this compound. We conclude that <b>IQ-1L</b> is more effective than <b>IQ-1S</b> in treating cerebral ischemia injury and thus represents a promising anti-inflammatory compound.https://www.mdpi.com/2227-9059/10/9/2119c-Jun <i>N</i>-terminal kinase11<i>H</i>-indeno[1,2-<i>b</i>]quinoxalin-11-oneoximeinterleukin-6nuclear factor-κBlithium salt |
| spellingShingle | Igor A. Schepetkin Galina A. Chernysheva Oleg I. Aliev Liliya N. Kirpotina Vera I. Smol’yakova Anton N. Osipenko Mark B. Plotnikov Anastasia R. Kovrizhina Andrei I. Khlebnikov Evgenii V. Plotnikov Mark T. Quinn Neuroprotective Effects of the Lithium Salt of a Novel JNK Inhibitor in an Animal Model of Cerebral Ischemia–Reperfusion Biomedicines c-Jun <i>N</i>-terminal kinase 11<i>H</i>-indeno[1,2-<i>b</i>]quinoxalin-11-one oxime interleukin-6 nuclear factor-κB lithium salt |
| title | Neuroprotective Effects of the Lithium Salt of a Novel JNK Inhibitor in an Animal Model of Cerebral Ischemia–Reperfusion |
| title_full | Neuroprotective Effects of the Lithium Salt of a Novel JNK Inhibitor in an Animal Model of Cerebral Ischemia–Reperfusion |
| title_fullStr | Neuroprotective Effects of the Lithium Salt of a Novel JNK Inhibitor in an Animal Model of Cerebral Ischemia–Reperfusion |
| title_full_unstemmed | Neuroprotective Effects of the Lithium Salt of a Novel JNK Inhibitor in an Animal Model of Cerebral Ischemia–Reperfusion |
| title_short | Neuroprotective Effects of the Lithium Salt of a Novel JNK Inhibitor in an Animal Model of Cerebral Ischemia–Reperfusion |
| title_sort | neuroprotective effects of the lithium salt of a novel jnk inhibitor in an animal model of cerebral ischemia reperfusion |
| topic | c-Jun <i>N</i>-terminal kinase 11<i>H</i>-indeno[1,2-<i>b</i>]quinoxalin-11-one oxime interleukin-6 nuclear factor-κB lithium salt |
| url | https://www.mdpi.com/2227-9059/10/9/2119 |
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