Low brain ascorbic acid increases susceptibility to seizures in mouse models of decreased brain ascorbic acid transport and Alzheimer's disease.
Low brain ascorbic acid increases susceptibility to seizures in mouse models of decreased brain ascorbic acid transport and Alzheimer's disease.
复制标题
DOI：
10.1016/j.eplepsyres.2014.11.017
复制
发表时间：
2015-02
影响因子：
2.2
通讯作者：
Harrison FE
中科院分区：
文献类型：
--
作者：
Warner TA;Kang JQ;Kennard JA;Harrison FE
癫痫发作是阿尔茨海默病的一种已知的并发症状，它们可以加速认知和神经病理功能障碍。次优维生素C（抗坏血酸）缺乏症，即不导致患者呈现坏血病的临床体征（例如嗜睡、出血、角化过度）的低水平，在膳食摄入不足的情况下容易获得，并且可能导致阿尔茨海默病和癫痫的氧化应激环境。本研究的目的是测试除了在淀粉样前体蛋白（APP）和早老素1（PSEN 1）基因中携带人类阿尔茨海默病突变之外，大脑抗坏血酸减少的小鼠是否改变了大脑中的电活动（脑电图; EEG），并且更容易受到药理学诱导的癫痫发作的影响。通过将APP/PSEN 1小鼠与钠维生素C转运体2（SVCT 2）杂合敲除小鼠杂交，降低了APP/PSEN 1小鼠的脑抗坏血酸。这些小鼠的脑抗坏血酸减少了约30%，这是由于为大脑提供ASC的SVCT 2水平较低。SVCT 2 +/−APP/PSEN 1小鼠在用红藻氨酸（10 mg/kg i. p.）处理后，抗坏血酸减少，脑中氧化应激增加，死亡率增加，癫痫发作潜伏期更快，并且在戊四唑（50 mg/kg i. p.）治疗此外，我们报告了一个全新的现象，即抗坏血酸缺乏单独增加红藻氨酸和戊四氮诱导癫痫发作的严重程度。这些数据表明，避免抗坏血酸缺乏症可能是特别重要的人群在癫痫和癫痫发作的风险增加，如阿尔茨海默氏病。
Seizures are a known co-occurring symptom of Alzheimer’s disease, and they can accelerate cognitive and neuropathological dysfunction. Sub-optimal vitamin C (ascorbic acid) deficiency, that is low levels that do not lead the sufferer to present with clinical signs of scurvy (e.g. lethargy, hemorrhage, hyperkeratosis), are easily obtainable with insufficient dietary intake, and may contribute to the oxidative stress environment of both Alzheimer’s disease and epilepsy. The purpose of this study was to test whether mice that have diminished brain ascorbic acid in addition to carrying human Alzheimer’s disease mutations in the amyloid precursor protein (APP) and presenilin 1 (PSEN1) genes, had altered electrical activity in the brain (electroencephalography; EEG), and were more susceptible to pharmacologically-induced seizures. Brain ascorbic acid was decreased in APP/PSEN1 mice by crossing them with sodium vitamin C transporter 2 (SVCT2) heterozygous knockout mice. These mice have an approximately 30% decrease in brain ascorbic acid due to lower levels of SVCT2 that supplies the brain with ASC. SVCT2+/−APP/PSEN1 mice had decreased ascorbic acid and increased oxidative stress in brain, increased mortality, faster seizure onset latency following treatment with kainic acid (10 mg/kg i.p.), and more ictal events following pentylenetetrazol (50 mg/kg i.p.) treatment. Furthermore, we report the entirely novel phenomenon that ascorbic acid deficiency alone increased the severity of kainic acid- and pentylenetetrazol-induced seizures. These data suggest that avoiding ascorbic acid deficiency may be particularly important in populations at increased risk for epilepsy and seizures, such as Alzheimer’s disease.
登录
查看更多内容
影响因子：
4.7
作者：
Minkeviciene, R.;Ihalainen, J.;Tanila, H.
通讯作者：
Tanila, H.
影响因子：
29
作者：
Vossel, Keith A.;Beagle, Alexander J.;Rabinovici, Gil D.;Shu, Huidy;Lee, Suzee E.;Naasan, Georges;Hegde, Manu;Cornes, Susannah B.;Henry, Maya L.;Nelson, Alexandra B.;Seeley, William W.;Geschwind, Michael D.;Gorno-Tempini, Maria L.;Shih, Tina;Kirsch, Heidi E.;Garcia, Paul A.;Miller, Bruce L.;Mucke, Lennart
通讯作者：
Mucke, Lennart
影响因子：
2.5
作者：
Xavier, S. M.;Barbosa, C. O.;Freitas, R. M.
通讯作者：
Freitas, R. M.
影响因子：
3.6
作者：
Harrison, F. E.;May, J. M.;McDonald, M. P.
通讯作者：
McDonald, M. P.
影响因子：
2.9
作者：
Rauca, C;Zerbe, R;Jantze, H
通讯作者：
Jantze, H