| Objective:Diabetic encephalopathy(DE),which is a chronic progress-ive disease, is the central nervous system complications of diabetes.The main clinical manifestations are mild or moderate cognitive impairment, including decline of the learning, memory and problem-solving abilities with the corresponding changes in brain morphology,neural electroph-ysiology and molecular biology.Clinical epidemiological study found that diabetes of different types has different cognitive function impairments,in patients with type 1 diabetes,cognitive dysfunction is characterized by a slowing of mental speed and a diminished mental flexibility,whereas learning and memory are spared;while in type 2 diabetes, the impairments are the changes in global cognition or individual cognitive domain.Up to now, the pathogenesis of diabetic encephalopathy is not yet clear.In the 80s of last century,the finding of a large number of brain insulin and insulin receptors existing in the hippocampus and cerebral cortex,which resulted the pathogenesis of diabetic encephalopathy may be related to the insulin signaling pathway in brain had been proposed.Moreover,studies confirmed that insulin has the effection of learning and memory enhancement on human and animal.The biological performance of brain insulin plays an important role in diabetic patients'central nervous system.Just like the peripheral insulin,insulin in brain plays a physiological role through the combination with insulin and insulin receptor substrate,then the insulin signal transduction pathway activated.When insulin and insulin receptor signaling pathway regulation is anomaly and insulin resistance(IR) existing,cognitive function of DM patients can be influenced and impair- ed.Evidences indicated that obesity-induced type 2 diabetes associated with the occurrence of endoplasmic reticulum stress;and a large number of studies have also suggested the endoplasmic reticulum stress related to insulin resistance.Those researches suggest that perhaps there is a relationship between the endoplasmic reticulum stress and insulin resistan-ce or a main risk factor during the type 2 diabetes progresses to the diabetic encephalopathy.Therefore,this study discussed the effect of Jinzhida Capsule on regulating the hippocampal insulin signaling pathway and the possible pathogenesis of type 2 diabetic encephalopathy.In recent years,with the proposed of the Multi-component of traditional Chinese medicine,following the idea and clinic experience,Professor Libin Zhan's research group created the Recipe-Jinzhida Capsule.The Recipe formed from 4 kinds of effective components,at a fixed ratio,which extracted from the natural herbal,the Green tea,Ginseng and so forth.Studies indicated that those medicines have anti-aging,improving learning and memory abilities effects on neuroprotection.Therefore this experiment will explore the role of how to improve the learning and memory impairment of type 2 diabetic encephalopathy rats after givng Jinzhida Capsule and its possible mechanisms.Methods:1.Specified pathogen-free(SPF) male Sprague Dawley(SD) rats were randomly divided into control group,diabetes encephalopathy model group,low dose treatment group with Jinzhida Capsule,middle dose treatment group with Jinzhida Capsule and high dose treatment group with Jinzhida Capsule,n=7.2.After 3d adaptive feed,control group rats still gave normal diet;while the other groups rats fed with high fat diet,4 weeks later, the rats fed with high fat diet were treat with intraperitoneal injection of 30mg/kg dose of 1% of streptozotocin(STZ) solution.72h later,measured the tail vein blood glucose randomly was measured,random blood glucose>16.7mmol/L identified as diabetic rats.At the 4th day after STZ injection the fasting serum insulin levels(FSI) was taken,at the 8th day the oral glucose tolerance test(OGTT) was given and at the 12th the insulin tolerance test(ITT) were carried.During the establishment of diabetic encephalopathy model,the general symptoms and signs of the rats were observed.Treatment was given to the model groups from the 8th week and the modeling factors were stopped.Diabetic encephalopathy rats was treated by low,middle and high dose Jinzhida Capsule,twice a day and 12 hours interval,for 5 weeks totally.3.At the 12th week,through the Step down test and the Morris water maze test, behavior was tested to evaluate the spatial learning and memory abilities.At the end of the experiment the rats hippocampus were obtained,then reserved in fridge.4.At the end, we detected protein expression of IRS-1,JNK and IRE1αin rat hippocampus by the Western blotting.Results:1.Rats with high-fat feeding began to gain weight from the 2th week.At 4th week,compared with control group rats,rats fed with high fat diet body weight was significantly increased(P<0.05).At the same time,the general conditions of all groups rats were good.There were no statistical significance between groups in food intake,water intake and rectal temp-erature.2.After the injection of STZ,diabetic rats'random blood glucose was significantly higher than the control group(P<0.01).The OGTT showed diabetic rats appeared significantly impaired glucose tolerance;the ITT also suggested that blood glucose decreased rate of the diabetic rats were slower than the control group ones.Compared with the control group rats,the FSI of the diabetes rats was significantly higher(P<0.05),which confirmed diabetes mullitus groups rats existing hyperinsulinemia.3.Behavioral results showed that type 2 diabetic encephalopathy rats' learning and memory declined(P<0.05),and only Jinzhida Capsule high dose group of diabetic encephalopathy rats'learning and memory were improved significantly(P<0.05).In our experiment,we also found that between the various Jinzhida Capsule group there were existing dose-effect relation-ships.4.Western blotting results suggested that compared with the control group,the diabetic encephalopathy rat'hippocampus'phosphorylation IRS-1,phosphorylated JNK and phosphorylated IREla protein expression increased significantly(P<0.05),while after treated with Jinzhida Capsule, only high dose group diabetic encephalopathy rats'hippocampus' phosphorylation IRS-1,phosphorylated JNK and phosphorylated IREla protein expression weakened(P<0.05).Conclusion:1.By high-fat diet combined with low dose intraperitoneal injection of STZ modeling method successfully established type 2 diabetic encephalopathy rat model,Behavioral experiments suggested that diabetic encephalopathy rats appeared learning and memory dysfunction.2.Jinzhida Capsule can significantly improve the type 2 diabetic encephalopathy rats'learning and memory abilities.3.The effect of Jinzhida Capsule improving the type 2 diabetic encephalopathy rats'learning and memory decline may be associated with the hippocampal insulin signaling pathway;Jinzhida Capsule can protect and maintain the insulin signaling pathway in the role of normal conduction.4.Jinzhida Capsule may regulate the insulin signaling pathway through reducing the phosphorylation levels of JNK,and IRE1αto decrease the endoplasmic reticulum stress. |
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