Sitagliptin, a dipeptidyl peptidase-4 inhibitor, improves recognition memory, oxidative stress and hippocampal neurogenesis and upregulates key genes involved in cognitive decline
Sitagliptin, a dipeptidyl peptidase-4 inhibitor, improves recognition memory, oxidative stress and hippocampal neurogenesis and upregulates key genes involved in cognitive decline
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DOI：
10.1111/dom.12432
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发表时间：
2015-04-01
影响因子：
5.8
通讯作者：
Flatt, P. R.
中科院分区：
文献类型：
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作者：
Gault, V. A.;Lennox, R.;Flatt, P. R.
目的：观察长期抑制二肽基肽酶-4(DPP-4)能否逆转高脂饲养小鼠的学习记忆障碍。方法：高脂饲养小鼠口服西格列汀(50 mg/kg体重)1次/d或生理盐水剂21d。另外一组标准饮食的小鼠接受生理盐水注射。定期测量能量摄入量、体重、血糖和胰岛素浓度。结果：西格列汀降低循环DPP-4活性，改善糖耐量，改善葡萄糖刺激的胰岛素分泌和胰岛素敏感性，降低血浆甘油三酯和胆固醇水平。抑制DPP-4改善了再认记忆(增加了1.2倍)，而不影响运动过多或焦虑水平。记忆和学习的改善与8-氧鸟嘌呤免疫染色的减少和海马区双皮质素染色的增加有关，这分别表明大脑氧化应激减少和海马神经发生增加。这些作用与显著上调海马GLP-1受体、葡萄糖依赖的胰岛素样多肽受体、突触素、sirtuin 1、糖原合成酶3β、超氧化物歧化酶2、核因子(红系衍生2)样2和血管内皮生长因子的基因表达有关。西格列汀治疗后血浆和脑内总GLP-1浓度显著升高，而脑组织中DPP-4活性无明显变化。结论：西格列汀可以逆转高脂饮食小鼠的记忆障碍，并与改善胰岛素敏感性、促进海马神经发生和减轻氧化应激有关。因此，DPP-4抑制剂可能通过改善代谢控制和减少认知功能的下降而表现出双重好处。
Aim: To examine whether prolonged dipeptidyl peptidase-4 (DPP-4) inhibition can reverse learning and memory impairment in high-fat-fed mice.Methods: High-fat-fed mice received oral sitagliptin (50 mg/kg body weight) once daily or saline vehicle over 21 days. An additional group of mice on standard chow received saline vehicle. Energy intake, body weight, glucose and insulin concentrations were measured at regular intervals. Glucose tolerance, insulin sensitivity, novel object recognition, DPP-4 activity, hormone analysis, hippocampal gene expression and histology were performed.Results: Sitagliptin decreased circulating DPP-4 activity and improved glucose tolerance, glucose-stimulated insulin secretion and insulin sensitivity, and reduced plasma triglycerides and cholesterol levels. DPP-4 inhibition improved recognition memory (1.2-fold increase) without affecting hypermoteric activity or anxiety levels. Improvement in memory and learning was linked to reduced immunostaining for 8-oxoguanine and increased doublecortin staining in the hippocampus, which were indicative of reduced brain oxidative stress and increased hippocampal neurogenesis, respectively. These effects were associated with significant upregulation of hippocampal gene expression of glucagon-like peptide-1 (GLP-1) receptor, glucose-dependent insulinotropic polypeptide receptor, synaptophysin, sirtuin 1, glycogen synthase kinase 3 beta., superdioxidemutase 2, nuclear factor (erythroid-derived 2)-like 2 and vascular endothelial growth factor. Total plasma and brain GLP-1 concentrations were significantly increased after sitagliptin therapy, whereas DPP-4 activity in brain tissue was not altered.Conclusion: These studies show that sitagliptin can reverse memory impairment in high-fat-fed mice and is also associated with improved insulin sensitivity, enhanced hippocampal neurogenesis and reduced oxidative stress. DPP-4 inhibitors may therefore exhibit dual benefits by improving metabolic control and reducing the decline in cognitive function.