Protective Effects of a New C-Jun N-terminal Kinase Inhibitor in the Model of Global Cerebral Ischemia in Rats

Abstract

c-Jun N-terminal kinase (JNK) is activated by various brain insults and is implicated in neuronal injury triggered by reperfusion-induced oxidative stress. Some JNK inhibitors demonstrated neuroprotective potential in various models, including cerebral ischemia/reperfusion injury. The objective of the present work was to study the neuroprotective activity of a new specific JNK inhibitor, IQ-1S (11H-indeno[1,2-b]quinoxalin-11-one oxime sodium salt), in the model of global cerebral ischemia (GCI) in rats compared with citicoline (cytidine-5′-diphosphocholine), a drug approved for the treatment of acute ischemic stroke and to search for pleiotropic mechanisms of neuroprotective effects of IQ-1S. The experiments were performed in a rat model of ischemic stroke with three-vessel occlusion (model of 3VO) affecting the brachiocephalic artery, the left subclavian artery, and the left common carotid artery. After 7-min episode of GCI in rats, 25% of animals died, whereas survived animals had severe neurological deficit at days 1, 3, and 5 after GCI. At day 5 after GCI, we observing massive loss of pyramidal neurons in the hippocampal CA1 area, increase in lipid peroxidation products in the brain tissue, and decrease in local cerebral blood flow (LCBF) in the parietal cortex. Moreover, blood hyperviscosity syndrome and endothelial dysfunction were found after GCI. Administration of IQ-1S (intragastrically at a dose 50 mg/kg daily for 5 days) was associated with neuroprotective effect comparable with the effect of citicoline (intraperitoneal at a dose of 500 mg/kg, daily for 5 days).The neuroprotective effect was accompanied by a decrease in the number of animals with severe neurological deficit, an increase in the number of animals with moderate degree of neurological deficit compared with control GCI group, and an increase in the number of unaltered neurons in the hippocampal CA1 area along with a significant decrease in the number of neurons with irreversible morphological damage. In rats with IQ-1S administration, the LCBF was significantly higher (by 60%) compared with that in the GCI control. Treatment with IQ-1S also decreases blood viscosity and endothelial dysfunction. A concentration-dependent decrease (IC50 = 0.8 ± 0.3 μM) of tone in isolated carotid arterial rings constricted with phenylephrine was observed after IQ-1S application in vitro. We also found that IQ-1S decreased the intensity of the lipid peroxidation in the brain tissue in rats with GCI. 2.2-Diphenyl-1-picrylhydrazyl scavenging for IQ-1S in acetonitrile and acetone exceeded the corresponding values for ionol, a known antioxidant. Overall, these results suggest that the neuroprotective properties of IQ-1S may be mediated by improvement of cerebral microcirculation due to the enhanced vasorelaxation, beneficial effects on blood viscosity, attenuation of the endothelial dysfunction, and antioxidant/antiradical IQ-1S activity.

Virtual Screening of Natural Products against Type II Transmembrane Serine Protease (TMPRSS2), the Priming Agent of Coronavirus 2 (SARS-CoV-2)

“…Other top-ranked drug-like compounds, potential inhibitor of TMPRSS2 [32], were the marine natural product excavatolide M (compound 2), a briarane-type diterpene, the cembranolide durumolide K (compound 6), predicted as toxic, the dibenzylcyclooctadiene lignan schisphenin A (compound 3) from Shisandra sphenanthera, the fungal decalactone dictyosphaeric acid A, obtained from the green alga Dictyosphaeria versluyii, with antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus faecium, and Candida albicans [38]. (compound 4), the endogenous cytidine (5 )-diphosphocholine, known as citicoline, (compound 5), with beneficial effects in transient global and focal cerebral ischemia [39], 5-methoxyhydnocarpin (compound 7), a Berberis species flavonolignan similar to silymarin and reported as a strong inhibitor of the NorA pump (an endogenous efflux transporter of S. aureus in the plasma membrane [40]), compound 8 from the free-floating algae known as Sargassum, the p-terphenyl antioxidant curtisian L (compound 9) from the wild mushroom Paxillus, microcarpin (compound 10), a bianthraquinone from Asphodelus microcarpus, the green tea polyphenol (-)-epicatechin 3-O-(3 -O-methyl) gallate (EGCG3"Me) (compound 11), and the aromatase inhibitor isogemichalcone B (compound 12), mainly from Artocarpus and Broussonetia genera. Among the remaining 73 compounds with a docking score comparable to that of the standard drug inhibitor, it is worth mentioning the active principles of popular herbs used in Ayurvedic traditional medicine and components of multi-ingredient food supplements formulations, i.e., fuscaxanthone A from Garcinia spp.…”

Endothelin 1-induced retinal ganglion cell death is largely mediated by JUN activation

“…Thinner retinal vessels and reduced blood flow have been reported in human [9][10][11][12]80 and animal models of glaucoma 5,6 . Notably, JNK-JUN signaling was found to contribute to neuronal death after ischemic insult to the rodent brain [47][48][49][50] and retina 51 . Therefore, it is possible that aberrant EDN signaling via mural cell-EDNRA contributes to reduced retinal blood flow in glaucoma, which could in turn perpetuate neurodegeneration via JNK-JUN signaling.…”

“…EDN ligands are the most potent vasoactive peptides, and EDN has been shown to cause vasoconstriction through EDNRA expressed by vascular smooth muscle cells 4,7,8,43,44 . Importantly, JUN-JNK signaling has been shown to mediate neuronal death after ischemic insult [47][48][49][50][51] . Therefore, it is possible that EDN1 elicits a hypoxic insult to the retina, which can ultimately lead to RGC death via JNK-JUN signaling.…”

“…Thinner retinal vessels and evidence of hypoxia have been demonstrated in animal models of chronic glaucoma 5,6,45,46 . Importantly, JUN was found be an important regulator of ischemia-induced neuronal death [47][48][49][50][51] . Thus, it is possible that EDN elicits a hypoxic insult to the retina via EDNRA to ultimately cause JUN-dependent RGC loss.…”

Role of c-Jun N-Terminal Kinases (JNKs) in Epilepsy and Metabolic Cognitive Impairment

“…Furthermore, Jang and colleagues reported that two JNK selective inhibitors, SU3327 and BI-78D3, which potently blocked JNK, protect against hepatotoxicity mediated by CCl4 (50 mg/kg, IP) [126]. Also, Plotnikov and colleagues demonstrated that a specific JNK inhibitor, IQ-1S (11H-indeno [1-b]-quinoxalin-11-one oxime sodium salt), which has a higher affinity for JNK3 compared with its affinity to JNK1/JNK2, showed a neuroprotective effect in models of ischemia in rat [127].…”