Correction of mitochondrial dysfunction with trimethoxy-substituted monocarbonyl curcumin analogues in experimental Alzheimer’s disease

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disease that is a terminal form of dementia with an alarming spread rate. The treatment of AD usually involves symptomatic therapy, but the research field for new medicines to correct AD focus on the pathogenetic keys of the disease, i.e., a mitochondrial dysfunction.The aim of the work was to evaluate the effect of trimethoxy-substituted monocarbonyl curcumin analogues on changes in the mitochondrial function of the hippocampus in AD rats.Materials and methods. AD was modeled in female Wistar rats by the injection of β-amyloid aggregates 1-42 into the CA1 part of the hippocampus. The tested compounds AZBAX4 and AZBAX6 at a dose of 20 mg/kg each, as well as the reference donepezil at a dose of 50 mg/kg, were administered orally for 30 days after the surgery. After the specified time had passed, the changes in the cellular respiration, a citrate synthase activity, cytochrome-c-oxidase, succinate dehydrogenase, and adenosine triphosphate (ATP) concentrations were evaluated in the mitochondrial fraction of the rat hippocampus.Results. During the study, it was shown that the use of AZBAX4 and AZBAX6 compounds contributed to an increase in the intensity of aerobic metabolism by 83.9 (p <0.05) and 35.9% (p <0.05), respectively, while reducing the activity of anaerobic one by 27.7 (p <0.05) and 20.6% (p <0.05), respectively. Against the background of the tested compounds AZBAX4 and AZBAX6 administration, there was also a significant increase in the activity of citrate synthase, succinate dehydrogenase and cytochrome-c-oxidase, as well as the level of ATP in the hippocampal tissue by 112.8 (p <0.05) and 117.1% (p <0.05), respectively. The use of donepezil led to a significant increase in the intensity of aerobic reactions – by 24.0% (p <0.05), a citrate synthase activity– by 80.0% (p <0.05) and the ATP concentration – by 68.5% (p <0.05). Against the background of the use of the analyzed substances, a decrease in the apoptosis-inducing factor and mitochondrial hydrogen peroxide is also worth noting.Conclusion. Based on the obtained data, it can be assumed that the use of AZBAX4 and AZBAX6 compounds contributes to an increase in the functional activity of the mitochondria of hippocampal cells of AD rats, while surpassing the reference donepezil. It is perspective to continue a further study of AZBAX4 and AZBAX6 compounds as possible medicines of a pathogenetic correction of AD.

Keywords

• alzheimer’s disease
• mitochondrial dysfunction
• curcumin analogues
• neuroprotection