Modulation of Oxidative Stress and Apoptosis by Alteration of Bioactive Lipids in The Pancreas, and Effect of Zinc Chelation in a Rat Model of Alzheimer's Disease

Abstract

Increasing epidemiological evidence highlights the association between systemic insulin resistance and Alzheimer's disease (AD). It is known that peripheral insulin resistance in the early stages of AD precedes and is a precursor to amyloid-β (Aβ) deposition. Although it is known that improving the CNS insulin sensitivity of AD patients is an important therapeutic goal and that the majority of insulin in the brain comes from the periphery, there has been little attention to the changes that occur in the pancreatic tissue of AD patients. Therefore, it is crucial to elucidate the mechanisms affecting insulin resistance in pancreatic tissue in AD. It is known that zinc (Zn+2) chelation is effective in reducing peripheral insulin resistance, cell apoptosis, cell death, and oxidative stress. Aims: This study aimed to determine the bioactive lipids in the pancreas in the Aβ oligomer-induced rat model to determine the changes in amylin (AIPP), oxidative stress, and apoptosis in pancreatic cells and to reveal the therapeutic effect of the Cyclo-Z agent on them. AD and ADC rats were intracerebroventricular (i.c.v.) Aβ1-42 oligomers. Cyclo-Z gavage was applied to ADC and SHC rats for 21 days. First of all, the effects of AIPP, bioactive ceramides, apoptosis and oxidative stress on the pancreatic tissue of AD group rats were evaluated. Then, the effect of Cyclo-Z treatment on these was examined. ELISA kit was used in biochemical analyses. AIPP and ceramide (CER) levels and CER/ sphingosine-1 phosphate (S1P) ratio were increased in the pancreatic tissue of AD rats. It also increased the level of CER kinase (CERK), which is known to increase the concentration of CER 1-phosphate (C1P), which is known to be toxic to cells in the presence of excessive CER concentration. Due to the increase in CER level, it was observed that apoptosis and oxidative stress increased in the pancreatic cells of AD group rats. Cyclo-Z, which has Zn+2 chelating properties, reduced AD model rats' AIPP level and oxidative stress and could prevent pancreatic apoptosis. Similar therapeutic effects were not observed in the pancreatic tissue of Cyclo-Z administered to the SH group. For this reason, it is thought that Cyclo-Z agent may have a therapeutic effect on the peripheral hyperinsulinemia observed in the early stages of AD disease and the resulting low amount of insulin transported to the brain, by protecting pancreatic cells from apoptosis and oxidative stress by regulating their bioactive metabolites.