Altered expression of brain monocarboxylate transporter 1 in models of temporal lobe epilepsy.
Altered expression of brain monocarboxylate transporter 1 in models of temporal lobe epilepsy.
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DOI：
10.1016/j.nbd.2011.08.001
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发表时间：
2012-01
影响因子：
6.1
通讯作者：
Eid, Tore
中科院分区：
文献类型：
--
作者：
Lauritzen, Fredrik;Perez, Edgar L.;Melillo, Eric R.;Roh, Jung-Min;Zaveri, Hitten P.;Lee, Tih-Shih W.;Wang, Yue;Bergersen, Linda H.;Eid, Tore
关键词：
单羧酸转运蛋白1（MCT1）促进单羧酸燃料（乳酸盐、丙酮酸盐和酮体）和酸性药物（如丙戊酸）跨细胞膜的转运。我们最近报道，在药物难治性颞叶癫痫（TLE）患者中，MCT1在致痫性海马结构的微血管上存在缺陷。为了进一步确定MCT 1在TLE病理生理学中的作用，我们使用免疫组织化学和体视学分析来定位和量化三种新型高度相关的TLE大鼠模型和非癫痫对照动物中海马结构中的转运蛋白。一种模型利用甲硫氨酸亚砜亚胺诱导脑谷氨酰胺合成酶缺乏症和复发性边缘癫痫发作，而两种模型采用一段穿孔通路刺激引起癫痫。在所有TLE模型中，MCT 1在海马结构的微血管上丢失，在星形胶质细胞上上调。值得注意的是，微血管上MCT1的丢失不是由于微血管密度的降低。在患有TLE的人类受试者和该疾病的几种动物模型中MCT1表达的相似性强烈表明该分子在TLE的发病机制中起关键作用。我们推测MCT1的下调可能通过致癫痫脑对酮体和抗癫痫药物的摄取受损而促进癫痫发作。我们还提出，MCT1在星形胶质细胞上的过表达可能导致这些细胞对单羧酸盐的摄取或释放增加，对脑代谢和兴奋性具有重要意义。这些假设现在可以在复制人类TLE关键特征的几种动物模型中进行严格的测试。
Monocarboxylate transporter 1 (MCT1) facilitates the transport of monocarboxylate fuels (lactate, pyruvate and ketone bodies) and acidic drugs, such as valproic acid, across cell membranes. We recently reported that MCT1 is deficient on microvessels in the epileptogenic hippocampal formation in patients with medication-refractory temporal lobe epilepsy (TLE). To further define the role of MCT1 in the pathophysiology of TLE, we used immunohistochemistry and stereological analysis to localize and quantify the transporter in the hippocampal formation in three novel and highly relevant rat models of TLE and in nonepileptic control animals. One model utilizes methionine sulfoximine to induce brain glutamine synthetase deficiency and recurrent limbic seizures, while two models employ an episode of perforant pathway stimulation to cause epilepsy. MCT1 was lost on microvessels and upregulated on astrocytes in the hippocampal formation in all models of TLE. Notably, the loss of MCT1 on microvessels was not due to a reduction in microvessel density. The similarities in MCT1 expression among human subjects with TLE and several animal models of the disease strongly suggest a critical role of this molecule in the pathogenesis of TLE. We hypothesize that the downregulation of MCT1 may promote seizures via impaired uptake of ketone bodies and antiepileptic drugs by the epileptogenic brain. We also propose that the overexpression of MCT1 on astrocytes may lead to increased uptake or release of monocarboxylates by these cells, with important implications for brain metabolism and excitability. These hypotheses can now be rigorously tested in several animal models that replicate key features of human TLE.
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DOI：
10.1152/ajpendo.1997.273.1.e207
发表时间：
1997-07-01
影响因子：
5.1
作者：
Gerhart, DZ;Enerson, BE;Drewes, LR
通讯作者：
Drewes, LR
DOI：
10.1016/j.ejpb.2008.05.022
发表时间：
2008-10-01
影响因子：
4.9
作者：
Fischer, Wiebke;Praetor, Katrin;Brandsch, Matthias
通讯作者：
Brandsch, Matthias
DOI：
10.1016/0005-2736(76)90120-6
发表时间：
1976-01-01
期刊：
BIOCHIMICA ET BIOPHYSICA ACTA
影响因子：
--
作者：
CREMER, JE;BRAUN, LD;OLDENDORF, WH
通讯作者：
OLDENDORF, WH
DOI：
10.1073/pnas.0409308102
发表时间：
2005-01-25
影响因子：
11.1
作者：
Eid, T;Lee, TSW;de Lanerolle, NC
通讯作者：
de Lanerolle, NC
影响因子：
3.6
作者：
CORNFORD, EM;BRAUN, LD;OLDENDORF, WH
通讯作者：
OLDENDORF, WH