| Background:Insulin resistance is one of important pathogenesy of diabetes.It goes through all of the process of diabetes:the source,genesis,development and end.Many epidemiologic studies have established that insulin resistance syndrome can increase the risk of cardiovascular disease and stroke by 300%and obviously their case fatality, also threaten of cognition function in old men.Increase activation of AGEs-RAGE pathway activation closely with ageing,cognitive handicap,peripheral neuropathy,it plays import role in the damage of the target organ in diabetes.Central cholinergic system is necessary and important in modulate the study and memory behavior to keep them on the normal level.Pioglitazone,a thiazolidinedione derivative,is a novel insulin-sensitizing agent for the treatment of insulin resistance.It demonstrated that Pioglitazone not only can activate PPARγbut also increase the tissular sensibility to Insulin.So it improves the insulin resistance.PPARγis reported has protection on brain by decrease the infarction volume in ischemia/reperfusion.Investigation on the mechanism of functional impairment in cognition and action of PPARγon central nervous system is seldom seen.Objective:1.To explore the effects and mechanisms of pioglitazone on cognition function and vigor of choline acetyltransferase in insulin resistance rats.2.To explore the effects of Pioglitazone on cognition function and AGEs-RAGE system in insulin resistance ratsMethod:6-8-week-old Wistar rats were fed with fructose to develop insulin resistance models for 4 weeks.IR rat model was randomly divided into IR group(n=13)and Pioglitazone(PIO)group(n=13).Rats in PIO group were given Pioglitazone 10mg/ (kg·d)by gavage for 12 weeks.The cognition ability of rats was assayed with Morris water maze test.The expression of advanced glycation end products were detected by immunofluorescence.Western blot was performed to detect the expression of PPARγ,Phospho -NF-κB and RAGE protein.The activity of choline acetyhransferase was detected by chemical coloration.Western blotting was performed to detect the expression of IGF-1 protein.Sections were stained with methyl aniline blue and cells in the hippocampal and cortex were observed with microscope.Result:1.12 weeks later,the quality,blood glucose and fasting insulin of rats Compared with NC group,the levels of quality in IR and PIO groups decreased but have no significantly difference(P＞0.05,P＞0.05).The level of fasting insulin in IR and PIO group increased significantly than NC group(P＜0.01,P＜0.05).The level of fasting insulin in PIO group decreased significantly than NC group(P＜0.01).2.The experimental result of Morris water maze testMorris water maze test showed that the escape latency was longer in IR group and PIO group than in NC group(P＜0.01,P＜0.05),and it was short in PIO group compared with IR group(P＜0.01).The expression of ChAT in IR group were lower than that in NC group.3.The experimental result of activities of ChATThe expression of ChAT in PIO was increased significantly compared with IR group.The expression of IGF-1 protein in IR and PIO groups was lower than it is in NC group(P＜0.01,P＜0.01).Compared with IR group,the expression of IGF-1 in PIO group was significant increased(P＜0.05).4.The expression of advanced glycation end products in hippocamp were detected by immunofluorescence.The expression index of AGEs in IR group were higher than that in NC group; It was decreased significantly in PIO group compared with IR group.5 Consequence of Western blotThe expression of RAGE and Phospho-NF-κB protein in IR and PIO groups were higher than in NC group.Compared with IR group,the expression of RAGE and Phospho-NF-κB in PIO group was significant decreased.The expression of PPARγprotein in IR and PIO groups was lower than it is in NC group(P＜0.05).Compared with IR group,the expression of PPARγin PIO group was significant increased (P＜0.05).The expression of IGF-1 protein in IR and PIO groups was lower than it is in NC group(P＜0.01,P＜0.01).Compared with IR group,the expression of IGF-1 in PIO group was significant increased(P＜0.05)6.The pathological measure of hippocamps in groups(Nissl's staining)Conclusion:1.Pathologic lesion occurred and cognition function injury in neurocyte in insulin resistance rats It is related to the effect of increasing the activation of ChAT and IGF-1.2.The expression of AGEs,RAGE Phospho-NF-κB protein in IR rats were increased but PPARγprotein decreased in corex of frontal lobe and hippocamp.The activation strengthens of AGEs-RAGE system is a possible mechanism of brain damage.The activation of AGEs-RAGE systemis related to upstate of the express of PPARγin biain.3.Pioglitazone therapy can improve cognition function in IR rat probably related to its effect of increasing the activation of ChAT and IGF-1and its effect of decreasing the activation of AGEs-RAGE system.Significance:The topic observed the changes of AGEs,RAGE,NF-κB,CHAT,IGF-1,and the change s of the escape latency among NC,IR and PIO groups by the Wastern blot,immunofluorescence,immunohistochemistry,chromatometry and so on.It approached the contribution of the exchanges of choline acetyltransferase, insulin-like growth factor-1 and AGEs-RAGE system in insulin resistance rats in pathogenesis of insulin resistance rats.This topic also evaluated the inhibitory action that Pioglitazone can play in the brain damage.Therefore,it is meaningful that the topic can play an important role in the theoretical evidence for the prevention and cure of clinical nervous system injury by insulin resistance...
|
PDF Full Text Request