Effect of 3-formylchromone derivatives on neuroinflammation reactions and JNK and NF-κB regulatory pathways

Abstract

BACKGROUND: Neuroinflammation is a significant component of the pathogenesis of cerebral ischemia. The JNK and NF-κB signaling pathways play a leading role in the progression of brain tissue inflammation, which may represent a promising target for therapeutic effects.

AIM: To evaluate the effect of new derivatives of 3-formylchromone on the course of neuroinflammation reactions and the activity of JNK and NF-κB translational pathways in brain tissue in rats with cerebral ischemia.

MATERIALS AND METHODS: Cerebral ischemia was modeled in Wistar rats by irreversible right-sided occlusion of the middle cerebral artery. The studied compounds and the reference (ethylmethylhydroxypyridine succinate) were administered per os at doses of 30 and 100 mg/kg, respectively. After 72 hours of ischemia, changes in the concentration of proinflammatory cytokines were evaluated in the cerebrospinal fluid: IL-6, IL-1β, IL-8 and TNF-α. The content of JNK and NF-κB in brain tissue was determined by enzyme immunoassay.

RESULTS: The use of the test compounds 3FC1, 3FC2, 3FC4 and 3FC5, as well as the reference medicine, contributed to a decrease in the content of proinflammatory markers in the liquor. At the same time, the most significant decrease was noted when the compound 3FC5 was administered to animals, namely, the concentration of IL-1β, IL-6, IL-8 and TNF-α was lower relative to similar indicators of the group of animals without treatment by 30.0% (p < 0.05); 64.5% (p < 0.05); 48.5% (p < 0.05) and 56.6% (p < 0.05), respectively. The use of the fluorine-containing compound 3FC3 did not significantly affect the course of brain tissue inflammation reactions in rats. Evaluation of changes in the activity of JNK and NF-κB showed that the studied substances inhibit the NF-κB translational pathway and do not affect JNK, which is probably due to the activation of these signaling pathways and the antioxidant potential of the studied molecules.

CONCLUSIONS: The use of compounds that are derivatives of 3-formylchromone in conditions of experimental cerebral ischemia contributes to the reduction of neuroinflammation reactions by inhibiting the NF-κB pathway, without affecting the activity of the JNK-dependent signaling system. The substance with the highest pharmacological effects is the compound 3FC5, which contains a spatially hindered phenolic hydroxyl in its structure.

Keywords

cerebral ischemia / neuroprotection / neuroinflammation / chromone derivatives

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