Neuroprotective Effects of a Novel Inhibitor of c-Jun N-Terminal Kinase in the Rat Model of Transient Focal Cerebral Ischemia

• Main Authors: 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
• Format: Article
• Language: English
• Published: MDPI AG 2020-08-01
• Series: Cells
• Subjects: 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
• Online Access: https://www.mdpi.com/2073-4409/9/8/1860

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.