Neuroprotective Effects of a Novel Inhibitor of c-Jun N-Terminal Kinase in the Rat Model of Transient Focal Cerebral Ischemia
A novel specific inhibitor of c-Jun N-terminal kinase, 11<i>H</i>-indeno[1,2-<i>b</i>]quinoxalin-11-one oxime sodium salt (IQ-1S), has a high affinity to JNK3 compared to JNK1/JNK2. The aim of this work was to study the mechanisms of neuroprotective activity of IQ-1S in the m...
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MDPI AG
2020-08-01
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| author | Mark B. Plotnikov Galina A. Chernysheva Vera I. Smolyakova Oleg I. Aliev Eugene S. Trofimova Eugene Y. Sherstoboev Anton N. Osipenko Andrei I. Khlebnikov Yana J. Anfinogenova Igor A. Schepetkin Dmitriy N. Atochin |
| author_facet | Mark B. Plotnikov Galina A. Chernysheva Vera I. Smolyakova Oleg I. Aliev Eugene S. Trofimova Eugene Y. Sherstoboev Anton N. Osipenko Andrei I. Khlebnikov Yana J. Anfinogenova Igor A. Schepetkin Dmitriy N. Atochin |
| author_sort | Mark B. Plotnikov |
| collection | DOAJ |
| description | A novel specific inhibitor of c-Jun N-terminal kinase, 11<i>H</i>-indeno[1,2-<i>b</i>]quinoxalin-11-one oxime sodium salt (IQ-1S), has a high affinity to JNK3 compared to JNK1/JNK2. The aim of this work was to study the mechanisms of neuroprotective activity of IQ-1S in the models of reversible focal cerebral ischemia (FCI) in Wistar rats. The animals were administered with an intraperitoneal injection of IQ-1S (5 and 25 mg/kg) or citicoline (500 mg/kg). Administration of IQ-1S exerted a pronounced dose-dependent neuroprotective effect, not inferior to the effects of citicoline. Administration of IQ-1S at doses of 5 and 25 mg/kg reduced the infarct size by 20% and 50%, respectively, 48 h after FCI, whereas administration of citicoline reduced the infarct size by 34%. The administration of IQ-1S was associated with a faster amelioration of neurological status. Control rats showed a 2.0-fold increase in phospho-c-Jun levels in the hippocampus compared to the corresponding values in sham-operated rats 4 h after FCI. Administration of IQ-1S at a dose of 25 mg/kg reduced JNK-dependent phosphorylation of c-Jun by 20%. Our findings suggest that IQ-1S inhibits JNK enzymatic activity in the hippocampus and protects against stroke injury when administered in the therapeutic and prophylactic regimen in the rat model of FCI. |
| first_indexed | 2024-03-10T17:45:46Z |
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| language | English |
| last_indexed | 2024-03-10T17:45:46Z |
| publishDate | 2020-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-3dc1138880274ce18240f8c48e38d1e92023-11-20T09:32:23ZengMDPI AGCells2073-44092020-08-0198186010.3390/cells9081860Neuroprotective Effects of a Novel Inhibitor of c-Jun N-Terminal Kinase in the Rat Model of Transient Focal Cerebral IschemiaMark B. Plotnikov0Galina A. Chernysheva1Vera I. Smolyakova2Oleg I. Aliev3Eugene S. Trofimova4Eugene Y. Sherstoboev5Anton N. Osipenko6Andrei I. Khlebnikov7Yana J. Anfinogenova8Igor A. Schepetkin9Dmitriy N. Atochin10Department of Pharmacology, Goldberg Research Institute of Pharmacology and Regenerative Medicine, Tomsk NRMC, 3 Lenin ave, 634028 Tomsk, RussiaDepartment of Pharmacology, Goldberg Research Institute of Pharmacology and Regenerative Medicine, Tomsk NRMC, 3 Lenin ave, 634028 Tomsk, RussiaDepartment of Pharmacology, Goldberg Research Institute of Pharmacology and Regenerative Medicine, Tomsk NRMC, 3 Lenin ave, 634028 Tomsk, RussiaDepartment of Pharmacology, Goldberg Research Institute of Pharmacology and Regenerative Medicine, Tomsk NRMC, 3 Lenin ave, 634028 Tomsk, RussiaDepartment of Pharmacology, Goldberg Research Institute of Pharmacology and Regenerative Medicine, Tomsk NRMC, 3 Lenin ave, 634028 Tomsk, RussiaDepartment of Pharmacology, Goldberg Research Institute of Pharmacology and Regenerative Medicine, Tomsk NRMC, 3 Lenin ave, 634028 Tomsk, RussiaDepartment of Pharmacology, Siberian State Medical University, 2 Moskovskiy tract, 634050 Tomsk, RussiaKizhner Research Center, Tomsk Polytechnic University, 634050 Tomsk, RussiaCardiology Research Institute, Tomsk NRMC, 111a Kievskaya St., 634012 Tomsk, RussiaKizhner Research Center, Tomsk Polytechnic University, 634050 Tomsk, RussiaKizhner Research Center, Tomsk Polytechnic University, 634050 Tomsk, RussiaA novel specific inhibitor of c-Jun N-terminal kinase, 11<i>H</i>-indeno[1,2-<i>b</i>]quinoxalin-11-one oxime sodium salt (IQ-1S), has a high affinity to JNK3 compared to JNK1/JNK2. The aim of this work was to study the mechanisms of neuroprotective activity of IQ-1S in the models of reversible focal cerebral ischemia (FCI) in Wistar rats. The animals were administered with an intraperitoneal injection of IQ-1S (5 and 25 mg/kg) or citicoline (500 mg/kg). Administration of IQ-1S exerted a pronounced dose-dependent neuroprotective effect, not inferior to the effects of citicoline. Administration of IQ-1S at doses of 5 and 25 mg/kg reduced the infarct size by 20% and 50%, respectively, 48 h after FCI, whereas administration of citicoline reduced the infarct size by 34%. The administration of IQ-1S was associated with a faster amelioration of neurological status. Control rats showed a 2.0-fold increase in phospho-c-Jun levels in the hippocampus compared to the corresponding values in sham-operated rats 4 h after FCI. Administration of IQ-1S at a dose of 25 mg/kg reduced JNK-dependent phosphorylation of c-Jun by 20%. Our findings suggest that IQ-1S inhibits JNK enzymatic activity in the hippocampus and protects against stroke injury when administered in the therapeutic and prophylactic regimen in the rat model of FCI.https://www.mdpi.com/2073-4409/9/8/1860neuroprotectioninhibitor of c-Jun N-terminal kinase11<i>H</i>-indeno[1,2-<i>b</i>]quinoxalin-11-one oxime sodium saltfocal cerebral ischemia-reperfusion |
| spellingShingle | Mark B. Plotnikov Galina A. Chernysheva Vera I. Smolyakova Oleg I. Aliev Eugene S. Trofimova Eugene Y. Sherstoboev Anton N. Osipenko Andrei I. Khlebnikov Yana J. Anfinogenova Igor A. Schepetkin Dmitriy N. Atochin Neuroprotective Effects of a Novel Inhibitor of c-Jun N-Terminal Kinase in the Rat Model of Transient Focal Cerebral Ischemia Cells neuroprotection inhibitor of c-Jun N-terminal kinase 11<i>H</i>-indeno[1,2-<i>b</i>]quinoxalin-11-one oxime sodium salt focal cerebral ischemia-reperfusion |
| title | Neuroprotective Effects of a Novel Inhibitor of c-Jun N-Terminal Kinase in the Rat Model of Transient Focal Cerebral Ischemia |
| title_full | Neuroprotective Effects of a Novel Inhibitor of c-Jun N-Terminal Kinase in the Rat Model of Transient Focal Cerebral Ischemia |
| title_fullStr | Neuroprotective Effects of a Novel Inhibitor of c-Jun N-Terminal Kinase in the Rat Model of Transient Focal Cerebral Ischemia |
| title_full_unstemmed | Neuroprotective Effects of a Novel Inhibitor of c-Jun N-Terminal Kinase in the Rat Model of Transient Focal Cerebral Ischemia |
| title_short | Neuroprotective Effects of a Novel Inhibitor of c-Jun N-Terminal Kinase in the Rat Model of Transient Focal Cerebral Ischemia |
| title_sort | neuroprotective effects of a novel inhibitor of c jun n terminal kinase in the rat model of transient focal cerebral ischemia |
| topic | neuroprotection inhibitor of c-Jun N-terminal kinase 11<i>H</i>-indeno[1,2-<i>b</i>]quinoxalin-11-one oxime sodium salt focal cerebral ischemia-reperfusion |
| url | https://www.mdpi.com/2073-4409/9/8/1860 |
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