Objective: Diabetes-associated cognitive deficits is characterized by long-term potentiation (LTP) decline in the hippocampus. DL-3-n-butylphthalide (NBP) is a novel agent exerting protective effect against ischemic brain. However, the effects of NBP on diabetes-associated cognitive deficits and underlying mechanisms are not fully clear. This study was designed to evaluate the effects of NBP on the cognitive deficits through activating CaMKII-mediated LTP process and protecting neuron structure of hippocampus in diabetic db/db mice. Methods: Male db/db mice were randomly divided into db/db group (n = 8) and db/db+NBP group (n = 8, 120mg/Kg NBP by gavage). Male db/m mice (n = 8) were included as control group. All animals were treated for 6 weeks. Morris Water Maze test was carried out to evaluate cognitive function. Electrophysiological recordings were performed to test LTP level. HE-staining and electron microscopy of hippocampus were used to observe structure change of neurons and synapse. RT-PCR and Western blot were used to assess the expression of CaMKII, NR2B, and GluR1. Results: Type 2 diabetes mellitus caused LTP decline, and significantly decreased NR2B, CaMKII, and GluR1 expression. Histological analysis showed that disorganized pyramidal cells, as well as degraded neuron and synapse ultrastructure in db/db mice. NBP treatment restored LTP and its associated proteins in db/db mice. The structure changes of hippocampal cells were partly reversed by NBP intervention. Conclusion: These results suggest that NBP ameliorates cognitive deficits induced by type 2 diabetes mellitus through improving CaMKII-mediated LTP and cell ultrastructure in the hippocampus. NBP is a potential therapeutic agent for diabetes-associated cognitive deficits. Abbreviations: NBP: DL-3-n-butylphthalide; LTP: long-term potentiation; CaMKII: calcium/calmodulin-dependent protein kinase II; NR2B: N-methyl-D-aspartic acid receptor subtype 2B; GluR1: α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor subtype 1.

中文翻译：

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DL-3-正丁基邻苯二甲酸酯（NBP）可改善糖尿病db / db小鼠海马中的认知缺陷和CaMKII介导的长期增强作用。

目的：糖尿病相关的认知功能障碍的特征在于海马的长期增强（LTP）下降。DL-3-正丁基酞（NBP）是一种新型药物，对缺血性脑具有保护作用。但是，NBP对糖尿病相关认知功能障碍和潜在机制的影响尚不完全清楚。这项研究旨在通过激活CaMKII介导的LTP过程和保护糖尿病db / db小鼠海马神经元结构来评估NBP对认知缺陷的影响。方法：雄性db / db小鼠随机分为db / db组（n = 8）和db / db + NBP组（n = 8，通过管饲法120mg / Kg NBP）。将雄性db / m小鼠（n ＝ 8）作为对照组。将所有动物治疗6周。进行莫里斯水迷宫测试以评估认知功能。进行电生理记录以测试LTP水平。海马HE染色和电镜观察神经元和突触的结构变化。RT-PCR和蛋白质印迹用于评估CaMKII，NR2B和GluR1的表达。结果：2型糖尿病导致LTP下降，并显着降低NR2B，CaMKII和GluR1表达。组织学分析表明，db / db小鼠的锥体细胞紊乱，神经元和突触超微结构退化。NBP处理可恢复db / db小鼠的LTP及其相关蛋白。NBP干预可部分逆转海马细胞的结构变化。结论：这些结果表明，NBP通过改善CaMKII介导的LTP和海马细胞超微结构，减轻了2型糖尿病引起的认知功能障碍。NBP是糖尿病相关认知功能障碍的潜在治疗剂。缩写：NBP：DL-3-正丁基邻苯二甲酸酯；LTP：长期增强；CaMKII：钙/钙调蛋白依赖性蛋白激酶II；NR2B：N-甲基-D-天冬氨酸受体亚型2B；GluR1：α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体亚型1。