Effect Of Naringenin On Brain Insulin Signaling And Cognitive Functions In ICV-STZ Induced Dementia Model Of Rats

ObjectiveTo investigate the effect of peroxisome proliferator-activated receptor γ(PPARγ) agonist-Naringenin (NAR) on the cognition, the expression ofmolecular in the insulin signaling, Aβ and Tau in the AD rat model, andexplore its potential mechanisms involving attenuate learning and memorydeficits. In addition, the study was designed to argue if naringenin canimprove AD model cognitive ability and how to improve AD rat model ofcognitive.MethodsRats(n=60) were randomly divided into the following groups:⑴sham-operated group(control) that received bilateral ICV injection ofsaline(5l on each side).⑵STZ-injected group(STZ) which received ICVinjection of STZ(3mg/kg).⑶low dose NAR-treated STZ group(NAR-L)(25mg/kg/day).⑷medium dose NAR-treated STZ group(NAR-M)(50mg/kg/day).⑸high dose NAR-treated STZ group(NAR-H)(100mg/kg/day).While sham rats received the same volume of vehicle, other rats were injected bilaterally with ICV-STZ (3mg/kg) and then supplementedwith NAR (25mg,50mg,100mg/kg, respectively) in NAR groups for threeweeks. Naringein was administered in the rats which were treated withintracerebroventricular (ICV) streptozotocin (STZ) induced dementia model.Rats of CON and STZ groups were given equal saline. On the21st dayfrom1st STZ injection, spatial learning and memory of animals were testedin Morris water maze. The expression of IDE, glycogen synthase kinese-3β(GSK-3β), phospho-GSK-3β, Tau and phospho-tau were measured bywestern-blot. Amyloid β-peptide (Aβ)42levels in the brain of the rats weretested by immunohistochemistry. The mRNA levels of insulin, insulinreceptor, PPARγ and IDE in cerebral cortex and hippocampus weremeasured by real time quantitative RT-PCR assays.Results1. The ICV-STZ injected rats did not have elevated blood glucose levels.There were no significant difference in body weight and brain weight amongeach group.2. Place navigation tests: the escape latency in the STZ group wassignificantly longer than that in the CON group. However, the latency in theNAR-groups was significantly decreased from the third day compared withSTZ group (p=0.003). There was no significant difference among the threeNAR-groups. Rats that were treated with NAR had better learning andmemory performance in the Morris water maze (MWM) test than rats were treated with saline. Spatial probe test: After the withdrawal of theplatform at fifth day, the time spent in the original platform quadrant wassignificantly longer in the CON group compared with STZ group (p<0.001).This showed that the memory capacity of STZ group was markedly reduced.NAR significantly pro-longed the time in the target quadrant compared withSTZ group (p=0.01). NAR supplementation attenuated STZ-inducedmemory deficits. There was no significant difference among three NAR-groups.3. NAR could up-regulate the PPARγ gene expression in cerebralcortex and hippocampus.4. The mRNA levels of insulin, insulin receptor, and IDE in cerebralcortex and hippocampus were decreased in STZ group compared with CONgroup. NAR can enhance the expression of insulin, insulin receptor, IDE andPPARγ. These effects were mediated by increased insulin and insulinreceptors expression in the brain, and suggested that insulin sensitizeragonist might have therapeutic efficacy in early AD.5. The study also demonstrated that NAR reversed ICV-STZ inducedTau hyper-phosphorylation in both hippocampus and cerebral cortex throughdown-regulation of glycogen synthase kinese-3β (GSK-3β) activity, a keykinase in the insulin signaling. Brain levels of A-beta, which were elevatedin ICV-STZ rats, were significantly reduced in NAR treated rats viaup-regulation of Insulin degrading enzyme (IDE). Conclusion1. ICV-STZ treatment can result in AD-like pathology via damageinsulin signaling. This study shows that insulin signaling plays an importantrole in the AD pathogenesis. The ICV-STZ induced dementia rat model canbe used to study AD mechanism.2. NAR can increase the mRNA levels of PPARγ.3. As a PPARγ agonist, NAR-mediated cognitive improvement doescorrelate with the expression of IDE and GSK-3β. These effects aremediated by increased insulin and insulin receptors expression in the brain.