Neuroprotective Effect And Mechanism Of Glucagon-like Peptide 1 Receptor Agonist On Hippocampal Neurons In Diabetic Rats

Objective:To investigate the neuroprotective effect and mechanism of glucagon-like peptide 1 receptor agonist liraglutide?LIR?on diabetic rats by observing the effect of LIR on the NF-?B inflammatory signal pathway and the expression of anti-oxidative stress proteins Klotho and PRX2 in hippocampus of diabetic rats.Methods:1 Selected 24 male SPF Goto-Kakizaki?GK?rats with random blood glucose greater than 11.1 mmol/L as the experimental group,and randomly divided into model group?DM,n=12?and liraglutide group?LIR,n=12?.Ten healthy male SPF Wistar rats with the same age and weight as GK rats were selected as normal control group?NC?.2After asaptively feeded for 2 weeks,LIR group was given LIR(400?g·kg^-1·d^-1,subcutaneous injection),NC group and DM group were given the same volume of saline,and continued to be administered for 8 weeks.3 The general data and biochemical indexes of rats were recorded.4 Morris water maze experiment Effects of LIR on learning and memory in DM rats was detected by MWM test.5 To prepare of specimens and test index Quickly separate the hippocampus after decapitation,-80? frozen.In hippocampus,HE staining observed the hippocampal neurons morphology,Western blotting method detected the expression of p-IKK?,p-NF-?B,NF-?B,Klotho and PRX2 in hippocampus.Results:1 General and biochemical data in different groups The levels of TC and LDL-C in DM group and LIR group were significantly higher than NC group,while the body weight was lower in NC group?F=21.321¹70.646,all P<0.01?The weight of rats in DM group decreased significantly([?373.41±20.37?vs?418.22±15.54?,t=104.350,P<0.01].The levels of TC and LDL-C between the DM group and LIR group had no statistical difference?all P>0.05?.The levels of HDL-C between the three groups had no statistical difference?P>0.05?.Compared with NC group,24 h urine volume,FBG,FINS,HbA_1c,TG and HOMA-IR of DM group were significantly increased?t=-104.057²57.382,all P<0.01?.The six indexes of LIR group were significantly lower than DM group?t=-67.158⁸0.023,all P<0.01??Table 1?.2 Morris water maze experiment results In the first to fourth days,the escape latency in DM group was significantly higher than NC group?t=74.618¹01.660,all P<0.01?.On the fifth day of space exploration experiment,the platform crossing and the time spent in target quadrant of DM rats were significantly shorter than NC group?t=-11.757,-79.467,all P<0.01?.The escape latency of LIR group was significantly shorter than DM group?t=66.436¹04.310,all P<0.01?,the platform crossing and the time spent in target quadrant were significantly increased?t=-7.520,-51.997,P<0.01??Figure 1?.3 HE staining results 1)In the NC group:The morphology of hippocampal neurons were noamal,the appearance of neurons was round or oval,the structure of neurons was integrity and arranged neatly.2)In the DM group:The morphology of hippocampal neurons were irregular and angular,the structure of neurons was destructed?nuclear pyknosis,chromatin condensation,cytoplasm reduction?and disordered arrangement,the number of normal neurons was significantly reduced compared with NC group.3)In the LIR group:The pathological changes were significantly reduced compared with the DM group?Figure 2?.4 Western blotting results The expression of p-IKK?and p-NF-?B protein in hippocampus of DM group were significantly higher than NC group.The expression of p-IKK?and p-NF-?B protein in LIR group were significantly lower than DM group?t=-44.859^-12.558,all P<0.01?.The expression of NF-?B in each group had no significant difference?t=-0.611,0.313,all P>0.05??Figure 3 and Figure 4?.The expression of NF-?B protein in cytoplasm of DM group was significantly lower than NC group?P<0.01?.The expression of NF-?B protein in cytoplasm of DM group was significantly higher than NC group?t=11.298,-47.355,all P<0.01?.The expression of NF-?B protein in nucleus was significantly lower than DM group?t=29.695,-46.683,all P<0.01??Figure 5 and Figure 6?.The expression of Klotho protein in hippocampus of DM group was significantly lower than NC group,and the expression of PRX2 protein was higher than NC group?t=8.298?-7.398,all P<0.01?.The expression of Klotho and PRX2 protein in hippocampus of LIR group were higher than DM group?t=-13.059?14.113,all P<0.01?.The expression of Klotho protein of LIR group was similar to NC group?t=-1.137,P>0.05?.The expression of PRX2 protein was significantly higher than NC group?t=-28.055,P<0.01??Figure 7 and Figure 8?.Conclusion 1 Liraglutide can improve glucose and lipid metabolism and insulin resistance in DM rats and has a weight-loss effect.2 The hippocampal neurons of DM rats were damaged,and the cognition of DM rats was impaired.3 Liraglutide may enhance the expression of antioxidant stress protein including Klotho and PRX2,by inhibiting NF-?B signaling pathway in hippocampus of DM rats,reduced oxidative stress and improved the injury of hippocampal neuronal in DM rats,played a neuroprotective effect,prevented and delayed the occurrence of DE.