Neuroprotective Effects of the Lithium Salt of a Novel JNK Inhibitor in an Animal Model of Cerebral Ischemia-Reperfusion.
Igor A SchepetkinGalina A ChernyshevaOleg I AlievLiliya N KirpotinaVera I Smol'yakovaAnton N OsipenkoMark B PlotnikovAnastasia R KovrizhinaAndrei I KhlebnikovEvgenii V PlotnikovMark T QuinnPublished in: Biomedicines (2022)
The 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 11 H -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 11 H -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.
Keyphrases
- cell death
- lps induced
- induced apoptosis
- signaling pathway
- cerebral ischemia
- cell cycle arrest
- inflammatory response
- molecular docking
- subarachnoid hemorrhage
- density functional theory
- cell proliferation
- nuclear factor
- anti inflammatory
- blood brain barrier
- randomized controlled trial
- gene expression
- heart failure
- coronary artery disease
- percutaneous coronary intervention
- acute coronary syndrome
- mass spectrometry
- dna binding
- binding protein
- platelet rich plasma
- capillary electrophoresis