Effect of Chalcone Derivative on Changes in Nox4-Dependent Mitochondrial Biogenesis of Brain Tissue in Rats with Focal Cerebral Ischemia

Introduction . NADP-oxidase 4 or NOX4 is an enzyme of the oxidase group that plays a significant role in the pathogenesis of ischemic stroke. First of all, NOX4 mediates the activation of oxidative stress and mitochondrial dysfunction, which makes it a promising pharmacotherapeutic target. Purpose. To evaluate the effect of the administration of 3-[(1E)-3-(3,4-dimethylphenyl)-3-oxoprope-1-en-1-yl]-4H-1-benzopyran-4-one on the change in NOX4-dependent mitochondrial biogenesis in rats with focal ischemia. Materials and Methods. Focal cerebral ischemia was modeled by irreversible right-sided occlusion of the middle cerebral artery in male Wistar rats. The analyzed compound - 3-[(1E)-3-(3,4-dimethylphenyl)-3-oxoprope-1-en-1-yl]-4H-1-benzopyran-4-one and the reference – ethylmethylhydroxypyridine succinate were administered orally at doses of 50 mg/kg and 100 mg/kg, respectively, on for 3 days from the moment of ischemia modeling. After the specified time, a change in the size of the necrosis zone was assessed in rats, a change in the activity of enzymes- biomarkers of mitochondrial biogenesis – succinate dehydrogenase and cytochrome-c-oxidase, as well as the NOX4 content were determined in the mitochondrial fraction. Results. The study showed that against the background of administration of ethylmethylhydroxypyridine succinate and 3-[(1E)-3-(3,4-dimethylphenyl)-3-oxoprope-1-en-1-yl]-4H-1-benzopyran-4-one to animals, a decrease in NOX4 content by 41.9% (p<0.05) and 42.8% (p<0.05) respectively was observed, which was accompanied by an increase in the activity of succinate dehydrogenase by 131.8% (p<0.05) and 137.5% (p<0.05), respectively, as well as cytochrome-c-oxidase by 83.1% (p<0.05) and 79.0% (p<0.05), respectively. It is worth noting that when using ethylmethylhydroxypyridine succinate and 3-[(1E)-3-(3,4-dimethylphenyl)-3-oxoprope-1-en-1-yl]-4H-1-benzopyran-4-oh, the brain necrosis zone in rats decreased by 17.6% (p<0.05) and 15.2% (p<0.05), respectively. Conclusion. It has been shown that oral administration of 3-[(1E)-3-(3,4-dimethylphenyl)-3-oxoprope-1-en-1-yl]-4H-1-benzopyran-4-one to animals with focal ischemia leads to a decrease in the area of brain necrosis, which may be based on suppression NOX4 and, accordingly, improved mitochondrial function.