Department of Experimental Medicine, Section of Pharmacology L. Donatelli, Second University of Naples, Naples, Italy.
Exp Gerontol. 2010 Mar;45(3):202-7. doi: 10.1016/j.exger.2009.12.004. Epub 2009 Dec 11.
We tested here the impact of a long-term inhibition of dipeptidyl peptidase-4 (DPP-4) with sitagliptin on the deposition of amyloid-beta within the brain and deficits in memory-related behavioral paradigms in a model of Alzheimer's disease (AD): double transgenic mice B6*Cg-Tg(APPswe,PSEN1dE9)85Dbo/J. Mice began to receive sitagliptin at 7 months of age. Three different dose of sitagliptin (5, 10 and 20 mg/kg), were administered daily for 12 weeks by gastric gavage. The treatments counteracted: (i) the memory impairment in the contextual fear conditioning test; (ii) increased the brain levels of GLP-1; (iii) produced significant reductions of nitrosative stress and inflammation hallmarks within the brain, as well as (iv) a significant diminution in the ultimate number and total area of betaAPP and Abeta deposits. All these effects much more evident for the dose of 20 mg/kg sitagliptin. The long-term inhibition of the endogenous DPP-4 enzymes with sitagliptin can significantly delay some forms of AD pathology, including amyloid deposition, when administered early in the disease course of a transgenic mouse model of AD.
我们在此测试了长期抑制二肽基肽酶-4（DPP-4）对 APP/PS1 双转基因阿尔茨海默病（AD）模型小鼠脑内β淀粉样蛋白沉积和记忆相关行为障碍的影响：B6*Cg-Tg(APPswe,PSEN1dE9)85Dbo/J 小鼠从 7 月龄开始接受西他列汀治疗。通过灌胃，每天给予小鼠 3 种不同剂量（5、10 和 20mg/kg）的西他列汀，持续 12 周。治疗可逆转：（i）在情景性恐惧条件反射测试中的记忆损伤；（ii）增加大脑中的 GLP-1 水平；（iii）减少大脑中的氧化应激和炎症标志物；（iv）β淀粉样前体蛋白和 Abeta 沉积的最终数量和总面积显著减少。所有这些效果在 20mg/kg 西他列汀剂量下更为明显。长期抑制内源性 DPP-4 酶可显著延缓 AD 病理的某些形式，包括淀粉样蛋白沉积，当在 AD 转基因小鼠模型的疾病早期给予治疗时。
