胰岛素逆转1型糖尿病脑病模型大鼠海马齿状回神经发生障碍与空间学习记忆异常的研究

Insulin replacement therapy reverses the abnormalities in spatial learning and memory as well as the neurogenesis disorders in the hippocampal dentate gyrus of rat with streptozotocin-induced type 1 diabetic encephalopathy

目的揭示海马齿状回神经发生与1型糖尿病脑病发病的相互关系以及用胰岛素干预后所发生的变化。方法分别用链脲佐菌素和胰岛素建立1型糖尿病脑病大鼠模型和胰岛素治疗大鼠模型,采用Morris水迷宫以及5-溴脱氧尿嘧啶（BrdU,一种神经干细胞DNA合成的标记物）单标、BrdU＋NF（神经丝,成熟神经元的标志物）双标、BrdU＋GFAP（胶质原纤维酸性蛋白,成熟星形胶质细胞的标志物）双标的免疫组织化学方法,测试大鼠的空间学习记忆能力,并在光镜下观察处于海马齿状回神经发生过程中的细胞存活、迁移和分化的程度。结果1型糖尿病脑病模型大鼠的空间学习能力,海马齿状回BrdU单标、BrdU＋NF双标和BrdU＋GFAP双标的阳性细胞数均明显下降（P〈0.01）;用胰岛素治疗后可提升以上各项指标几乎接近正常水平（P〈0.01）,但各种阳性细胞形态以及细胞迁移的方向、路径和终点均不受到明显的影响。结论个体内长期缺乏胰岛素,导致海马齿状回神经干细胞生存率和分化率下降,可能是诱发1型糖尿病脑病的一个因素;尽早用胰岛素进行干预可逆转神经发生障碍和学习记忆异常,这将有利于防治该脑病的发生。

Objective to explore the relationships between type 1 diabetic encephalopathy and neurogenesis in the hippocampal dentate gyrus,and the effects of insulin replacement therapy on the disease.Methods Streptozotocin-induced type 1 diabetic encephalopathy and insulin replacement therapy models of Wistar rats were respectively developed.Morris water maze,bromodeoxyuridine（BrdU）,BrdU＋NF（neurofilament）,and BrdU＋GFAP（glial fibrillary acidic protein） immunohistochemistry were used to detect the spatial learning and memory,the survival,migration and differentiation of neural stem cells in the hippocampal dentate gyrus of model rats.Results The abilities in spatial learning and memory,the numbers of BrdU-positive,BrdU＋NF-positive and BrdU＋GFAP-positive cells in encephalopathy group rats were significantly decreased（P〈0.01）,while insulin administration raised the above parameters near the normal levels of the control group rats（P〈0.01）.However,the migration of neural stem cells in the dentate gyrus was not affected even under the condition suffering from diabetic encephalopathy.Conclusion The decreases in cell survival rate and cell differentiation rate induced by a long-termed lack of insulin may result in the development of type 1 diabetic encephalopathy,indicating that early insulin replacement therapy can reverse the impairments in the dentate gyrus neurogenesis,and can help to prevent and to treat diabetic encephalopathy.