Investigation of Cyclo-Z Therapeutic Effect on Insulin Pathway in Alzheimer's Rat Model: Biochemical and Electrophysiological Parameters.

ABSTRACT

Cyclo (his-pro-CHP) plus zinc (Zn+2) (Cyclo-Z) is the only known chemical that increases the production of insulin-degrading enzyme (IDE) and decreases the number of inactive insulin fragments in cells. The aim of the present study was to systematically characterize the effects of Cyclo-Z on the insulin pathway, memory functions, and brain oscillations in the Alzheimer's disease (AD) rat model. The rat model of AD was established by bilateral injection of Aß42 oligomer (2,5nmol/10µl) into the lateral ventricles. Cyclo-Z (10mg Zn+2/kg and 0.2mg CHP/kg) gavage treatment started seven days after Aß injection and lasted for 21 days. At the end of the experimental period, memory tests and electrophysiological recordings were performed, which were followed by the biochemical analysis. Aß42 oligomers led to a significant increase in fasting blood glucose, serum insulin, Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) and phospho-tau-Ser356 levels. Moreover, Aß42 oligomers caused a significant decrement in body weight, hippocampal insulin, brain insulin receptor substrate (IRS-Ser612), and glycogen synthase kinase-3 beta (GSK-3ß) levels. Also, Aß42 oligomers resulted in a significant reduction in memory. The Cyclo-Z treatment prevented the observed alterations in the ADZ group except for phospho-tau levels and attenuated the increased Aß42 oligomer levels in the ADZ group. We also found that the Aß42 oligomer decreased the left temporal spindle and delta power during ketamine anesthesia. Cyclo-Z treatment reversed the Aß42 oligomer-related alterations in the left temporal spindle power. Cyclo-Z prevents Aß oligomer-induced changes in the insulin pathway and amyloid toxicity, and may contribute to the improvement of memory deficits and neural network dynamics in this rat model.