| OBJECTIVE To observe the effect of glucagon-like peptide-1 receptor agonist exenatide on the cognitive function and to explore the possible mechanisms in diabetic rats.METHODS The male Wistar rats were randomly divided into control group, diabetes group and exenatide group. The rat model of diabetes was established by intraperitoneal injection of streptozotocin(STZ)(60mg/kg). Exenatide(1nmol/kg/d) was administered by subcutaneous injection for eight weeks. The other rats were administered with the same volume of saline. The body weight(BW) of rats was measured and the general condition of rats was observated. The glucose oxidase method and radioimmunoassay were respectively used to measure the levels of fasting blood sugar(FBS) and fasting blood insulin(FBI). Morris water maze test was used to investigate the cognitive function. The structure of hippocampus was observated by Hematoxylin-Eosin(H-E) staining. The density of nerve cell in the hippocampus was counted by Image Pro Plus 6.0 software. Tunel staining was used to test the apoptosis in the hippocampus. Western blot assay was used to measure the expressions of apoptosis related gene including Bax, Bcl-2 and caspase-3, insulin receptor(IR), insulin receptor substrates-1(IRS-1) and insulin receptor substrates-2(IRS-2) in hippocampus.RESULTS(1) The polydipsia, polyphagia and hyperdiuresis phenomenon were occurred in the rats of diabetes model group. The hair was brown and dull, spirits was drooping, the activity of rats was decreased and the response to external stimuli was slow in the diabetes model group.(2) In the experiments fourth and eighth weeks, compared with the control group, the BW of rats was significantly decreased, the FBS was significantly increased and the level of FBI was significantly decreased in diabetes model group(all P﹤0.05). In the experiments fourth and eighth weeks, compared with the diabetes model group, the BW of rats was significantly increased, the FBS was significantly decreased and the level of FBI was significantly increased in the exenatide group(all P﹤0.05).(3) Compared with the control group, the time required to find the platform was significantly increased(P<0.05), the residence time at central area and the number of passing the original platform were significantly decreased in the diabetes model group(all P<0.05). Compared with the diabetes model group, the time required to find the platform was significantly decreased(P<0.05), the residence time at central area and the number of passing the original platform were significantly increased in the exenatide group(all P<0.05).(4) In the control group, the contours of neuron in the hippocampus was limpid, cells were arranged in neat, the cytoplasmic staining was uniform and the nucleolus was clearly visible. The contours of neuron in the hippocampus was vague, nerve cells had different degrees of nuclear pyknosis, the size of neural cell was decreased, the nerve cells were scarce in part region and nerve cells in the hippocampus arranged in disorder which CAl region was the most obvious in diabetes model group. The above-mentioned pathological changes were significantly reduced, nuclear pyknosis and reduce of cell size did not find and nerve cells were arranged in order in the exenatide group.(5) Compared with the control group, the densities of nerve cells in CA1 and CA2 region of gyrus hippocampi were significantly decreased(all P<0.05) in the diabetes model group. Compared with the diabetes model group, the densities of nerve cells in CA1 and CA2 region of gyrus hippocampi were significantly increased in the exenatide group(all P﹤0.05).(6) Compared to the control group, the rate of apoptosis of nerve cells in CA1 region of gyrus hippocampi was significantly increased in the diabetes model group(P<0.05). Compared to the diabetes model group, the rate of apoptosis of nerve cells in CA1 region of gyrus hippocampi were significantly decreased in the exenatide group(P﹤0.05).(7) Compared to the control group, the expressions of Bax and caspase-3 in the hippocampus were significantly up-regulated(all P<0.05), the expression of Bcl-2 were significantly down-regulated(P<0.05) and Bax/Bcl-2 were significantly increased(P<0.05) in the diabetes model group. Compared to the diabetes model group, the expressions of Bax and caspase-3 in the hippocampus were significantly down-regulated(all P<0.05), the expression of Bcl-2 were significantly up-regulated(P<0.05) and Bax/Bcl-2 were significantly decreased(P<0.05) in the exenatide group.(8) The expressions of insulin receptor, IRS-1 and 2 in the hippocampus were significantly down-regulated(all P<0.05) in the diabetes model group compared to the control group. The expressions of insulin receptor, IRS-1 and 2 in the hippocampus were significantly increased(P<0.05) in the exenatide group compared to the diabetes model group.CONCLUSIONS Glucagon-like peptide-1 receptor agonist exenatide improves the cognitive function in rats with diabetes, which the mechanism may be related to up-regulation of insulin receptor, IRS-1 and 2 expressions and inhibition of apoptosis of nerve cell in the hippocampus. |
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