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

Abstract

BackgroundCyclo (his-pro-CHP) plus zinc (Zn + 2 ) (Cyclo-Z) is the only chemical agent known to stimulate IDE synthesis and reduction of inactive cellular insulin fragments. ObjectivesThe aim of this study was to characterize the effects of Cyclo-Z on insulin pathway, memory functions and brain oscillations in the Alzheimer's disease (AD) rat model. MethodsThe rat model of AD was established by bilateral injection of Aβ42 oligomer (2,5nmol/10µl) into the lateral ventricles. Cyclo-Z (10mg Zn + 2 /kg and 0,2mg CHP/kg, daily) was administered orally by gavage for 21 days. At the end of the experimental period, memory tests and electrophysiological recordings were performed which followed by the biochemical analysis. ResultsAβ42 oligomers led to a signi cant increase in fasting blood glucose, serum insülin, Homeostatic Model Assessment for Insulin Resistance(HOMA-IR) and phospho-tau-Ser356 levels. Moreover, Aβ42 oligomers caused a signi cant decrement in body weight, hippocampal insulin, brain insulin receptor substrate(IRS-Ser612), and glycogen synthase kinase-3 beta(GSK-3β) levels. Also, Aβ42 oligomers resulted in a signi cant reduction in memory. The Cyclo-Z treatment prevented the observed alterations in the ADZ group except for phospho-tau levels and attenuated the increased Aβ42 oligomers levels in the ADZ group. We also found that the Aβ42 oligomer decreased the left temporal spindle and delta power during ketamine anesthesia. Cyclo-Z treatment reversed the Aβ42 oligomer-related alterations in the left temporal spindle power. ConclusionsCyclo-Z prevents Aβ oligomer-induced changes in the insulin pathway, amyloid toxicity, and may contribute to the improvement of memory de cits and neural network dynamics in this rat model.

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

“…At the same time, it was found that there was a hyperinsulinemia state against hyperglycemia and peripheral insulin resistance that occurred in the AβO-induced early AD rat model [34]. Considering that chronic peripheral hyperinsulinemia reduces the amount of insulin transported to the brain by suppressing BBB insulin receptors, it is an expected result that patients with AD will reduce brain insulin concentration [37,34]. Many of the well-documented mechanisms that induce neuronal and synaptic degeneration in the AD brain are triggered and propagated due to the effects of soluble oligomers of the Aβ peptide on neurons and glia [38].…”

“…Aβ can bind to the insulin receptor competitively and induce insulin resistance [32]. Studies have also found that hyperglycemia and hyperinsulinemia, which develop in the initial stages of AD, maybe early biomarkers of AD [33,34]. In patients with AD, insulin resistance in the periphery is positively associated with brain Aβ accumulation in the frontal and temporal regions [35].…”

“…The central infusion of AβOs leads to peripheral insulin resistance [36]. At the same time, it was found that there was a hyperinsulinemia state against hyperglycemia and peripheral insulin resistance that occurred in the AβO-induced early AD rat model [34]. Considering that chronic peripheral hyperinsulinemia reduces the amount of insulin transported to the brain by suppressing BBB insulin receptors, it is an expected result that patients with AD will reduce brain insulin concentration [37,34].…”