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Effects of Pioglitazone on Congnition Function and AGEs-RAGE Signal Transmission in Brain Tissue of Insulin Resistance in Rats

Author: ZhengMin
Tutor: LiuXuePing
School: Shandong University
Course: Geriatrics
Keywords: Pioglitazone Insulin Resistance Acknowledge Glycation end products Choline acetyltransferase Insulin-like growth factor-1
CLC: R749.1
Type: Master's thesis
Year: 2008
Downloads: 137
Quote: 0
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Abstract

Research background of insulin resistance (insulin resistance, IR) diabetes pathogenesis, throughout the incidence of diabetes, the development of the whole process, but also lead to the root causes of the complications of diabetes. Epidemiological studies have shown: 3-fold increased risk of insulin resistance syndrome in patients with cardiovascular disease and stroke, mortality was significantly higher. The study results showed that insulin resistance is an important risk factor for cognitive decline. Cognitive impairment the early mainly as a decline in learning and memory function. The cholinergic system is an important regulatory role in learning and memory behavior, to maintain its normal function, is a necessary condition to maintain mammalian learning and memory. Insulin resistance and hyperinsulinemia, lipid disorders as the main feature. And long-term high blood sugar can cause the body to a variety of substances glycosylation reaction produces advanced glycation end products (advanced glycation endproducts, AGEs). Recent studies have shown: advanced glycation end product - advanced glycation end product receptor (receptor for advanced glycation end product, RAGE) pathway activation is one of the mechanisms of the the diabetes target organ damage, the pathways were enhanced with aging, The close relationship between cognitive impairment and peripheral neuropathy. Of pioglitazone are thiazolidinediones, TZDs, is a novel insulin sensitizer improve insulin resistance by increasing tissue sensitivity to insulin and lower blood sugar levels, and its biological effects mainly through activation of peroxisome proliferator activated receptor γ (Peroxisome Proliferator-activatedreceptor gammar, PPARγ). Studies have reported that PPARγ agonists can reduce ischemia-reperfusion infarct volume, cerebral protective effects. Domestic been on insulin resistance mechanisms of cognitive decline and PPARγ agonists on central AGEs-RAGE signaling pathway impact study reported. Purpose (1) to explore the high-fructose-induced insulin resistant rats cognitive function, choline acetyltransferase (cholineacetyltransferase, ChAT) activity and insulin-like growth factor -1 (insulin-like growth factor-1, IGF-1) changes (2) to explore the high-fructose-induced insulin resistance AGEs-RAGE damage pathway in rat brain tissue changes. (3) explore Pioglitazone (Pioglitazone, PIO) role in insulin resistance in the rat brain damage and mechanisms 45, 6 to 8 weeks of age, clean healthy male Wistar rats (purchased from the Experimental Animal Center of Shandong University), weighing 180 to 200g, adaptive feeding for one week, from 10 randomly selected as the normal group (NC), standard rodent chow and drinking tap water; remaining 35 standard rodent diet and drinking 10% fructose water (see Reaven GM) produced insulin resistance model. After four weeks, the insulin resistance index (insulin resistance index, IRI) will create a successful insulin resistance model animals were randomly divided into insulin resistance group (IR) and pioglitazone group (PIO group). Pioglitazone intervention methods: detection model after the success of the IR group and PIO group continue standard rodent diet, drinking 10% fructose water to the end of the experiment, the PIO group at the same time intragastric administration of 10 mg / (kg · d) NC group and the the IR group fed corresponding volume of saline, a total of 12 weeks. 12 weeks after the intervention, the following tests: 1. Determination rats body weight, blood glucose, insulin levels, insulin resistance index; 2 by Morris water maze test, the rats were observed cognitive function change; 3. Colorimetric determination ChAT activity in brain tissue; 4. immunofluorescence detection of brain tissue AGEs expression; 5.Western blot brain tissue of PPARγ, RAGE, phosphorylation of nuclear transcription factor-κB (Phospho-NF-κB p65 Ser536), IGF-1 expression . Brain tissue slices Nissl rats in each group to change the results of an observation the rats brain tissue morphology and Nissl body weight, fasting blood glucose, insulin levels interfere with the weekend of the 12th IR group, PIO group rat body weight, fasting blood glucose compared with NC group tended to increase, but the difference was not statistically significant (P> 0.05); the the IR group insulin levels compared with NC group was significantly higher (P <0.01), the PIO group insulin levels compared with NC group (P <0.05); the the PIO group insulin levels significantly lower than the IR group (P <0.01). 2 Morris water maze test scores compare IR group evade incubation period than the NC group (P <0.01) was significantly longer the PIO group escape latency compared with NC group extend (P <0.05), PIO group escape latency compared with the IR group was significantly shorter (P <0.01) 3. choline acetyltransferase activity compared with the NC group (69.042 ± 7.6603) comparing IR group (36.9225 ± 5.0859) ChAT activity decreased, the difference was significant (P <0.01). The PIO group (50.0825 ± 6.2224) ChAT activity increased compared with IR group, the difference was statistically significant (P <0.05), but still lower than the NC group (P <0.01). Immunofluorescence detection of AGEs expression NC group hippocampus, cortex cells arranged in dense, visible expression of AGEs in the cytoplasm, weak expression; IR group cells were loose, AGEs expression was strongly positive; compared with IR group, PIO group of cells arranged closely; intensity of AGEs express, the decrease in the number of positive cells. The 5.Western blotting detection of brain tissue of PPARγ, of RAGE, Phospho-NF-kappa B, IGF-1 expression ① IR and PIO groups RAGE protein expression levels compared with NC group increased 1.68 times the NC group were 1.24 times; with IR group the PIO group RAGE protein levels decreased by 26.2% compared, the difference was statistically significant (P <0.01). Phosphorylation of the ② IR and PIO groups of NF-κB protein expression levels compared with NC group increased 1.58 times the NC group were 1.27 times; compared with IR group, PIO group phosphorylation of NF-κB protein expression levels decreased 19.6 %, the difference was statistically significant (P <0.01). ③ IR and PIO groups PPARγ protein expression levels compared with NC group lower were 0.72% of the NC group, 0.89%; compared with IR group, the PIO group of PPARγ protein expression levels, 1.23 times the IR group, the difference was statistically significant (P <0.05). The ④ IR and PIO groups of IGF-1 protein expression levels lower than the normal control group were 35.7% and 48.05% of the NC group; compared with IR group, the the PIO group of IGF-1 protein expression levels, IR group 1.35 times, the difference was statistically significant (P <0.05) 6. Nissl morphological changes: NC group morphologically normal neurons of various brain regions, the nucleus membrane and nucleolus clear; the IR mice of frontal cortex hippocampal cells arranged sparse cell gap increases, the cytoplasmic Nissl reduce or disappear. PIO group than in the IR group improved neuronal cells still neatly arranged, densely rich Nissl bodies in the cytoplasm. Conclusion 1. Insulin resistance rat nerve cells occurs pathological damage, cognitive decline and brain tissue IGF-1 expression may decline ChAT activity decreased neuronal apoptosis Acetylcholine (Acetylcholine, ACh) release reduce related. Insulin resistance rat cerebral cortex, hippocampus AGEs, RAGE, phosphorylation of NF-κB protein expression; reduced expression of PPARγ. Prompted AGEs-RAGE and downstream pathway activation may be involved in the process of brain tissue damage. AGEs-RAGE pathways were enhanced with the decreased PPARγ activity. 3. Pioglitazone increased by promoting the expression of PPARγ to enhanced central ChAT activity increased IGF-1 expression, maintaining the cholinergic nerve function, learning and memory dysfunction in rat model with improved role. While pioglitazone by PPARγ AGEs-RAGE pathway inhibition, thus improving the cognitive function of the insulin-resistant rats. The significance of this issue through the use of the Western blot, immunofluorescence, Nissl staining, colorimetric method to observe the ketone before and after the intervention pioglitazone insulin resistance in rat brain tissue of AGEs, RAGE, NF-κB, PPARγ, ChAT expression of IGF-1 change and the rats escape latency of changes of IGF-1, ChAT changes in rat brain tissue AGEs-RAGE pathway in insulin resistance role in the mechanism of brain damage, as well as pioglitazone on insulin resistance in rat brain tissue insulin resistance injury and AGEs-RAGE pathway, the prevention and treatment of central nervous system injury provide a theoretical basis for clinical insulin resistance.

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