FTY720 (Fingolimod) Attenuates Beta-amyloid Peptide (Aβ42)-Induced Impairment of Spatial Learning and Memory in Rats
FTY720 (Fingolimod) Attenuates Beta-amyloid Peptide (Aβ42)-Induced Impairment of Spatial Learning and Memory in Rats
复制标题
DOI：
10.1007/s12031-013-9979-6
复制
发表时间：
2013-07-01
影响因子：
3.1
通讯作者：
Dargahi, Leila
中科院分区：
文献类型：
--
作者：
Asle-Rousta, Masoumeh;Kolahdooz, Zeynab;Dargahi, Leila
脑中脂质代谢失衡和神经酰胺与S1 P比例增加被认为在阿尔茨海默病（AD）病理学中的淀粉样蛋白生成、神经炎症反应和神经元凋亡中发挥作用。FTY 720，免疫调节鞘氨醇1-磷酸（S1 P）类似物，最近获得了兴趣，因为它的CNS导向作用。FTY 720除了在多发性硬化中具有免疫调节作用外，在不同的脑缺血模型中具有抗炎和神经保护作用。在本研究中，我们研究了FTY 720在AD大鼠模型中的作用。通过双侧海马内注射β-淀粉样肽（A β（42））诱导记忆障碍，并通过Morris水迷宫测试进行检查。采用Nissl染色和Western blotting法检测海马组织损伤程度和caspase-3活性。长期每日施用FTY 720（1 mg/kg，i. p.，14天）显著减轻A β（42）诱导的学习和记忆障碍，并防止海马神经元损伤以及caspase-3活化。这些数据首次表明FTY 720在A β（42）诱导的神经毒性中具有恢复记忆丧失的有益作用，并且还表明S1 P受体和信号通路可能为治疗AD提供潜在靶点。
Imbalanced lipid metabolism and increase in the ceramide-to-S1P ratio in the brain have been postulated to play a role in amyloidogenesis, neuroinflammatory reactions, and neuronal apoptosis in Alzheimer's disease (AD) pathology. FTY720, the immunomodulatory sphingosine 1-phosphate (S1P) analog, has recently gained interest because of its CNS-directed effects. In addition to its immunomodulatory functions in multiple sclerosis, FTY720 possesses anti-inflammatory and neuroprotective roles in different cerebral ischemia models. In the present study, we examined the effects of FTY720 in a rat model of AD. Memory deficit was induced by bilateral intrahippocampus injection of beta-amyloid peptide (A beta(42)) and examined through the Morris water maze test. The extent of histological injury in the hippocampus and the activation of caspase-3 were determined respectively by Nissl staining and Western blotting. Chronic daily administration of FTY720 (1 mg/kg, i.p., 14 days) significantly attenuated the A beta(42)-induced learning and memory impairment and prevented the hippocampus neuronal damage as well as caspase-3 activation. These data show for the first time that FTY720 has a beneficial effect in restoring memory loss in A beta(42)-induced neurotoxicity and also suggest that S1P receptors and signaling pathways may provide a potential target for the treatment of AD.