Long-term atorvastatin treatment leads to alterations in behavior, cognition, and hippocampal biochemistry.
Long-term atorvastatin treatment leads to alterations in behavior, cognition, and hippocampal biochemistry.
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DOI：
10.1016/j.bbr.2014.03.014
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发表时间：
2014-07-01
影响因子：
2.7
通讯作者：
Head BP
中科院分区：
文献类型：
--
作者：
Schilling JM;Cui W;Godoy JC;Risbrough VB;Niesman IR;Roth DM;Patel PM;Drummond JC;Patel HH;Zemljic-Harpf AE;Head BP
膜/脂筏（Membrane/Lipid Rafts，MLR）是质膜微区，在神经元信号转导和突触发育/稳定中起重要作用。他汀类药物抑制HMG-CoA还原酶，这是甲羟戊酸生物合成中的限速酶，甲羟戊酸是通过甲羟戊酸途径生成胆固醇的前体。由于他汀类药物对神经元和认知功能的影响存在争议，我们研究了长期阿托伐他汀治疗（5 mg/kg/d，经口灌胃7个月）对小鼠行为、认知和脑生化的影响。我们假设长期他汀类药物治疗会改变脂筏和认知功能。阿托伐他汀治疗导致行为缺陷，如在基本探索（旷场活动）和认知功能（巴恩斯迷宫，惊吓反应）范例中测量的，而不损害整体运动功能（转子杆）。此外，MLR相关蛋白（syntaxin-1α和synaptophysin）和突触后密度蛋白95（PSD 95）的整体变化也被观察到。观察到的MLR定位的突触前囊泡蛋白syntaxin-1α和突触素的减少表明了观察到的他汀类药物相关认知功能损害的分子机制，并且临床文献已经提出了这一点。
Membrane/lipid rafts (MLR) are plasmalemmal microdomains that are essential for neuronal signaling and synaptic development/stabilization. Statins inhibit HMG-CoA reductase, the rate-limiting enzyme in the biosynthesis of mevalonic, a precursor to cholesterol via the mevalonate pathway. Because there has been controversy over the effects of statins on neuronal and cognitive function, we investigated the impact of long-term atorvastatin treatment (5mg/kg/d for 7 months by oral gavage) on behavior, cognition, and brain biochemistry in mice. We hypothesized that long-term statin treatment would alter lipid rafts and cognitive function. Atorvastatin treatment resulted in behavioral deficits as measured in paradigms for basic exploration (open field activity) and cognitive function (Barnes maze, startle response) without impairment in global motor function (Rotor Rod). Furthermore, significant changes in MLR-associated proteins (syntaxin-1α and synaptophysin) and a global change of post-synaptic density protein-95 (PSD95) were observed. The observed decreases in the MLR-localized pre-synaptic vesicle proteins syntaxin-1α and synaptophysin suggest a molecular mechanism for the statin-associated impairment of cognitive function that was observed and that has been suggested by the clinical literature.
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DOI：
10.1038/npp.2008.205
发表时间：
2009-05
期刊：
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
影响因子：
--
作者：
通讯作者：
--
影响因子：
4.1
作者：
Galatti, Laura;Polimeni, Giovanni;Spina, Edoardo
通讯作者：
Spina, Edoardo
影响因子：
8.9
作者：
Swiger, Kristopher J.;Manalac, Raoul J.;Martin, Seth S.
通讯作者：
Martin, Seth S.
影响因子：
168.9
作者：
Jick, H;Zornberg, GL;Drachman, DA
通讯作者：
Drachman, DA
影响因子：
3.3
作者：
Schmitt, U.;Tanimoto, N.;Leube, R. E.
通讯作者：
Leube, R. E.