Silibinin Attenuates Amyloid β25-35 Peptide-Induced Memory Impairments: Implication of Inducible Nitric-Oxide Synthase and Tumor Necrosis Factor-α in Mice
Silibinin Attenuates Amyloid β25-35 Peptide-Induced Memory Impairments: Implication of Inducible Nitric-Oxide Synthase and Tumor Necrosis Factor-α in Mice
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DOI：
10.1124/jpet.109.155069
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发表时间：
2009-10-01
影响因子：
3.5
通讯作者：
Nabeshima, T.
中科院分区：
文献类型：
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作者：
Lu, P.;Mamiya, T.;Nabeshima, T.
在阿尔茨海默病（AD）中，淀粉样肽的沉积总是与氧化应激和炎症反应相关。水飞蓟宾（silybin）是一种从草本植物水飞蓟中提取的黄酮类化合物，具有有效的抗炎和抗氧化活性。然而，目前尚不清楚水飞蓟宾是否改善淀粉样蛋白β（A β）肽诱导的神经毒性。在这项研究中，我们研究了水飞蓟宾对小鼠侧脑室注射A β肽（25-35）（A β（25 - 35））诱导的恐惧条件记忆缺陷、炎症反应和氧化应激的影响。用水飞蓟宾（2、20和200 mg/kg p.o.，每天一次，持续8天）。在线索和情境恐惧条件反射测试中评价记忆功能（第6天）。检查海马和杏仁核中的硝基酪氨酸水平（第8天）。在A β（25-35）注射后2小时测量海马和杏仁核中诱导型一氧化氮合酶（iNOS）和肿瘤坏死因子-α（TNF-α）的mRNA表达。我们发现，水飞蓟宾显着减弱记忆缺陷所造成的β A（25-35）在线索和上下文的恐惧条件反射测试。水飞蓟宾显著抑制A β诱导的海马和杏仁核中硝基酪氨酸水平的增加（25-35）。这些区域的硝基酪氨酸水平与记忆表现呈负相关。此外，实时RT-PCR显示，水飞蓟宾抑制A β诱导的海马和杏仁核中iNOS和TNF-α mRNA的过表达（25-35）。这些发现表明，水飞蓟宾（i）通过改善A β（25-35）诱导的氧化应激和炎症反应减轻记忆障碍，（ii）可能是AD药物的潜在候选药物。
In Alzheimer's disease (AD), the deposition of amyloid peptides is invariably associated with oxidative stress and inflammatory responses. Silibinin (silybin), a flavonoid derived from the herb milk thistle, has potent anti-inflammatory and antioxidant activities. However, it remains unclear whether silibinin improves amyloid beta (A beta) peptide-induced neurotoxicity. In this study, we examined the effect of silibinin on the fear-conditioning memory deficits, inflammatory response, and oxidative stress induced by the intracerebroventricular injection of A beta peptide(25-35) (A beta(25-35)) in mice. Mice were treated with silibinin (2, 20, and 200 mg/kg p.o., once a day for 8 days) from the day of the A beta(25-35) injection (day 0). Memory function was evaluated in cued and contextual fear-conditioning tests (day 6). Nitrotyrosine levels in the hippocampus and amygdala were examined (day 8). The mRNA expression of inducible nitric-oxide synthase (iNOS) and tumor necrosis factor-alpha (TNF-alpha) in the hippocampus and amygdala was measured 2 h after the A beta(25-35) injection. We found that silibinin significantly attenuated memory deficits caused by A beta(25-35) in the cued and contextual fear-conditioning test. Silibinin significantly inhibited the increase in nitrotyrosine levels in the hippocampus and amygdala induced by A beta(25-35). Nitrotyrosine levels in these regions were negatively correlated with memory performance. Moreover, real-time RT-PCR revealed that silibinin inhibited the overexpression of iNOS and TNF-alpha mRNA in the hippocampus and amygdala induced by A beta(25-35). These findings suggest that silibinin (i) attenuates memory impairment through amelioration of oxidative stress and inflammatory response induced by A beta(25-35) and (ii) may be a potential candidate for an AD medication.