Department of Geriatrics, the First Affiliated Hospital, Chongqing Medical University, China.
Alzheimer Dis Assoc Disord. 2011 Oct-Dec;25(4):352-63. doi: 10.1097/WAD.0b013e31820ce536.
Diabetic encephalopathy is clinically characterized by acquired behavior and cognitive dysfunction but its pathogenesis is not clear. This study aimed to explore the pathogenesis of diabetic encephalopathy and the mechanisms of ghrelin to ameliorate cognitive dysfunction in diabetic rats. Thirty-six streptozotocin diabetic rat models were established; 12 weeks later, all the rats were randomly divided into 3 groups [diabetic model group (D), ghrelin treatment group (T1), and ghrelin and D-lys-3-GHRP-6 treatment group (T2)] of 12 each. Twelve normoglycemic rats were classified in the normal group (N). Learning and memory behaviors were measured using a spatial version of the Morris water maze test. The brain-derived neurotrophic factor (BDNF), cAMP responsive element binding protein (CREB), phosphorylated CREB (p-CREB), phosphorylated ERK1/2 (p-ERK1/2), caspase-3, and Bcl-xl protein expressions in the hippocampi of all the rats were detected using immunohistochemistry. The mRNA expressions of BDNF, CREB, and caspase-3 were examined using reverse transcription-polymerase chain reaction. The hippocampus neuronal apoptosis was measured by terminal deoxynucleotidyl transferase dUTP nick end labeling method. We found that learning and memory level in the ghrelin treatment group improved significantly, expression of Bcl-xl, BDNF, CREB, p-CREB, and p-ERK1/2 in the hippocampus was increased in the ghrelin treatment group, and the number of apoptotic neurons in the hippocampus decreased remarkably. Our results showed that the changes of BDNF, CREB, and hippocampus neuronal apoptosis might be involved in the pathogenesis of diabetic encephalopathy. We suggested that ghrelin improved cognitive ability in streptozotocin-induced diabetic rats by improving the expressions of BDNF and CREB and by attenuating hippocampus neuronal apoptosis. The effects of ghrelin depend on the receptor of ghrelin, GHSR-1a, and ERK1/2 pathway.
糖尿病性脑病的临床特征为获得性行为和认知功能障碍，但发病机制尚不清楚。本研究旨在探讨糖尿病性脑病的发病机制以及ghrelin改善糖尿病大鼠认知功能障碍的机制。建立 36 只链脲佐菌素诱导的糖尿病大鼠模型；12 周后，所有大鼠随机分为 3 组[糖尿病模型组（D）、ghrelin 治疗组（T1）和 ghrelin 和 D-lys-3-GHRP-6 治疗组（T2）]，每组 12 只。12 只正常血糖大鼠分为正常组（N）。采用空间版 Morris 水迷宫试验测量学习和记忆行为。采用免疫组织化学法检测各组大鼠海马脑源性神经营养因子（BDNF）、cAMP 反应元件结合蛋白（CREB）、磷酸化 CREB（p-CREB）、磷酸化 ERK1/2（p-ERK1/2）、半胱氨酸天冬氨酸蛋白酶-3（caspase-3）和 Bcl-xl 蛋白的表达。采用逆转录-聚合酶链反应（RT-PCR）检测 BDNF、CREB 和 caspase-3 的 mRNA 表达。采用末端脱氧核苷酸转移酶 dUTP 缺口末端标记法（TUNEL）检测海马神经元凋亡。结果发现，ghrelin 治疗组学习记忆水平显著提高，ghrelin 治疗组海马 Bcl-xl、BDNF、CREB、p-CREB 和 p-ERK1/2 表达增加，海马神经元凋亡数量显著减少。结果表明，BDNF、CREB 和海马神经元凋亡的变化可能参与了糖尿病性脑病的发病机制。我们推测，ghrelin 通过提高 BDNF 和 CREB 的表达以及减轻海马神经元凋亡来改善链脲佐菌素诱导的糖尿病大鼠的认知能力。ghrelin 的作用依赖于 ghrelin 的受体 GHSR-1a 和 ERK1/2 通路。
