Prediger Rui D S, Franco Jeferson L, Pandolfo Pablo, Medeiros Rodrigo, Duarte Filipe S, Di Giunta Gabriella, Figueiredo Cláudia P, Farina Marcelo, Calixto João B, Takahashi Reinaldo N, Dafre Alcir L
Departamento de Farmacologia, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, 88040-900 Florianópolis, SC, Brazil.
Behav Brain Res. 2007 Feb 27;177(2):205-13. doi: 10.1016/j.bbr.2006.11.032. Epub 2006 Dec 27.
Considerable evidence supports the role of oxidative stress in the pathogenesis of Alzheimer's disease (AD). Previous studies suggest that the central nervous system (CNS) administration of beta-amyloid peptide, the major constituent of senile plaque in AD, induces oxidative stress in rodents which may contribute to the learning and memory deficits verified in the beta-amyloid model of AD. In the present study, we compared the effects of a single intracerebroventricular (i.c.v.) injection of aggregated beta-amyloid peptide-(1-40) (Abeta(1-40)) (400pmol/mouse) on spatial learning and memory performance, synaptic density and the glutathione (GSH)-dependent antioxidant status in adult male C57BL/6 and Swiss albino mice. Seven days after Abeta(1-40) administration, C57BL/6 and Swiss mice presented similar spatial learning and memory impairments, as evaluated in the water maze task, although these impairments were not found in Abeta(40-1)-treated mice. Moreover, a similar decline of synaptophysin levels was observed in the hippocampus (HC) and prefrontal cortex (PFC) of both Swiss and C57BL/6 mice treated with Abeta(1-40), which suggests synaptic loss. C57BL/6 mice presented lower levels of glutathione-related antioxidant defences (total glutathione (GSH-t) levels, glutathione peroxidase (GPx) and glutathione reductase (GR) activity) in the HC and PFC in comparison to Swiss mice. Despite the reduced basal GSH-dependent antioxidant defences observed in C57BL/6 mice, Abeta(1-40) administration induced significant alterations in the brain antioxidant parameters only in Swiss mice, decreasing GSH-t levels and increasing GPx and GR activity in the HC and PFC 24h after treatment. These results indicate strain differences in the susceptibility to Abeta(1-40)-induced changes in the GSH-dependent antioxidant defences in mice, which should be taken into account in further studies using the Abeta model of AD in mice. In addition, the present findings suggest that the spatial learning and memory deficits induced by beta-amyloid peptides in rodents may not be entirely related to glutathione-dependent antioxidant response.
大量证据支持氧化应激在阿尔茨海默病（AD）发病机制中的作用。先前的研究表明，向中枢神经系统（CNS）注射β-淀粉样肽（AD中淀粉样老年斑的主要成分）可在啮齿动物中诱导氧化应激，这可能导致在AD的β-淀粉样肽模型中证实的学习和记忆缺陷。在本研究中，我们比较了成年雄性C57BL/6和瑞士白化小鼠单次脑室内（i.c.v.）注射聚集的β-淀粉样肽-（1-40）（Aβ（1-40））（400pmol/小鼠）对空间学习和记忆能力、突触密度以及谷胱甘肽（GSH）依赖性抗氧化状态的影响。在给予Aβ（1-40）七天后，C57BL/6和瑞士小鼠在水迷宫任务中表现出相似的空间学习和记忆障碍，尽管在接受Aβ（40-1）处理的小鼠中未发现这些障碍。此外，在用Aβ（1-40）处理的瑞士和C57BL/6小鼠的海马体（HC）和前额叶皮质（PFC）中均观察到突触素水平有类似下降，这表明存在突触丢失。与瑞士小鼠相比，C57BL/6小鼠在HC和PFC中的谷胱甘肽相关抗氧化防御水平较低（总谷胱甘肽（GSH-t）水平、谷胱甘肽过氧化物酶（GPx）和谷胱甘肽还原酶（GR）活性）。尽管在C57BL/6小鼠中观察到基础GSH依赖性抗氧化防御降低，但给予Aβ（1-40）仅在瑞士小鼠中诱导了脑抗氧化参数的显著变化，在处理后24小时，HC和PFC中的GSH-t水平降低，GPx和GR活性增加。这些结果表明，小鼠对Aβ（1-40）诱导的GSH依赖性抗氧化防御变化的易感性存在品系差异，在进一步使用小鼠AD的Aβ模型进行研究时应予以考虑。此外，目前的研究结果表明，β-淀粉样肽在啮齿动物中诱导的空间学习和记忆缺陷可能并不完全与GSH依赖性抗氧化反应相关。
