Upregulation of lactate dehydrogenase A in a chronic model of temporal lobe epilepsy
Upregulation of lactate dehydrogenase A in a chronic model of temporal lobe epilepsy
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DOI：
10.1111/epi.16488
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发表时间：
2020-05-01
期刊：
影响因子：
5.6
通讯作者：
Inoue, Tsuyoshi
中科院分区：
文献类型：
--
作者：
Sada, Nagisa;Suto, Shogo;Inoue, Tsuyoshi
生酮饮食治疗对耐药性癫痫有效。由于其抗癫痫作用与乳酸脱氢酶（LDH）相关，因此可以通过靶向乳酸脱氢酶进行药物开发。在啮齿动物模型中，通过抑制LDH抑制癫痫发作;然而，尚不清楚癫痫发作是否会改变脑中的LDH。在本研究中，我们研究了LDH亚基（LDHA和LDHB）在慢性颞叶癫痫模型中的表达，在该模型中，通过向小鼠海马中微量注射红藻氨酸诱导癫痫发作。使用蛋白质印迹分析，我们发现，LDHA的表达增加在海马的慢性癫痫发作模型，而LDHB的表达没有。在该癫痫发作模型中，海马中的乳酸水平也增加，表明LDH酶活性升高。此外，抑制LDHA抑制自发性阵发性放电在体内的慢性癫痫发作模型。总之，我们的研究结果表明，慢性癫痫发作增加LDHA，反之，抑制LDHA抑制癫痫发作，这支持LDHA作为一个分子靶点，为开发新的抗癫痫药物。
The ketogenic diet treatment is effective for drug-resistant epilepsy. Because its antiepileptic effect is associated with lactate dehydrogenase (LDH), drug development is possible by targeting LDH enzymes. Seizures in rodent models are suppressed by inhibiting LDH; however, it remains unclear whether LDH in the brain is changed by seizures. In the present study, we examined the expression of LDH subunits (LDHA and LDHB) in a chronic model of temporal lobe epilepsy, in which seizures were induced by the microinjection of kainate into the mouse hippocampus. Using Western blot analyses, we found that LDHA expression was increased in the hippocampus of the chronic seizure model, whereas LDHB expression was not. Lactate levels in the hippocampus were also increased in this seizure model, suggesting elevated LDH enzymatic activities. Furthermore, the inhibition of LDHA suppressed spontaneous paroxysmal discharges in vivo in the chronic seizure model. In conclusion, our results show that chronic seizures increase LDHA, and conversely, the inhibition of LDHA suppresses seizures, which supports LDHA as a molecular target for the development of new antiepileptic drugs.