当前位置: X-MOL 学术Front. Mol. Neurosci. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Sarcosine Suppresses Epileptogenesis in Rats With Effects on Hippocampal DNA Methylation.
Frontiers in Molecular Neuroscience ( IF 3.5 ) Pub Date : 2020-05-06 , DOI: 10.3389/fnmol.2020.00097
Hai-Ying Shen 1 , Landen Weltha 1 , John M Cook 1 , Raey Gesese 1 , Wakaba Omi 1 , Sadie B Baer 1 , Rizelle Mae Rose 1 , Jesica Reemmer 1 , Detlev Boison 1
Affiliation  

Epileptogenesis is a common consequence of brain insults, however, the prevention or delay of the epileptogenic process remains an important unmet medical challenge. Overexpression of glycine transporter 1 (GlyT1) is proposed as a pathological hallmark in the hippocampus of patients with temporal lobe epilepsy (TLE), and we previously demonstrated in rodent epilepsy models that augmentation of glycine suppressed chronic seizures and altered acute seizure thresholds. In the present study we evaluated the effect of the GlyT1 inhibitor, sarcosine (aka N-methylglycine), on epileptogenesis and also investigated possible mechanisms. We developed a modified rapid kindling model of epileptogenesis in rats combined with seizure score monitoring to evaluate the antiepileptogenic effect of sarcosine. We used immunohistochemistry and Western blot analysis for the evaluation of GlyT1 expression and epigenetic changes of 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) in the epileptogenic hippocampi of rats, and further evaluated expression changes in enzymes involved in the regulation of DNA methylation, ten-eleven translocation methylcytosine dioxygenase 1 (TET1), DNA-methyltransferase 1 (DNMT1), and DNMT3a. Our results demonstrated: (i) experimental evidence that sarcosine (3 g/kg, i.p. daily) suppressed kindling epileptogenesis in rats; (ii) the sarcosine-induced antiepileptogenic effect was accompanied by a suppressed hippocampal GlyT1 expression as well as a reduction of hippocampal 5mC levels and a corresponding increase in 5hmC; and (iii) sarcosine treatment caused differential expression changes of TET1 and DNMTs. Together, these findings suggest that sarcosine has unprecedented disease-modifying properties in a kindling model of epileptogenesis in rats, which was associated with altered hippocampal DNA methylation. Thus, manipulation of the glycine system is a potential therapeutic approach to attenuate the development of epilepsy.



中文翻译:

肌氨酸抑制大鼠海马DNA甲基化的癫痫发生。

癫痫发生是脑损伤的常见结果,然而,预防或延迟癫痫发生过程仍然是重要的医学难题。甘氨酸转运蛋白1(GlyT1)的过表达被认为是颞叶癫痫(TLE)患者海马中的病理标志,我们先前在啮齿类癫痫模型中证明了甘氨酸的增加抑制了慢性癫痫发作并改变了急性癫痫发作阈值。在本研究中,我们评估了GlyT1抑制剂肌氨酸(又名N-甲基甘氨酸)对癫痫发生的作用,并研究了可能的机制。我们开发了一种改进的大鼠癫痫发生快速点燃模型,结合癫痫发作评分监测功能来评估肌氨酸的抗癫痫作用。我们使用免疫组化和蛋白质印迹分析来评估大鼠癫痫海马中GlyT1的表达以及5-甲基胞嘧啶(5mC)和5-羟甲基胞嘧啶(5hmC)的表观遗传学变化,并进一步评估参与调节DNA的酶的表达变化甲基化,十一个11易位甲基胞嘧啶双加氧酶1(TET1),DNA-甲基转移酶1(DNMT1)和DNMT3a。我们的结果证明:(i)实验证据表明肌氨酸(3 g / kg,每天腹腔注射)可抑制大鼠的点燃性癫痫发生。(ii)肌氨酸诱导的抗癫痫发生作用伴随着海马GlyT1表达的抑制,海马5mC水平的降低和5hmC的相应升高;(iii)肌氨酸治疗引起TET1和DNMT的差异表达变化。一起,这些发现表明,肌氨酸在大鼠癫痫发生的点燃模型中具有空前的疾病改变特性,这与海马DNA甲基化改变有关。因此,操纵甘氨酸系统是减轻癫痫发展的潜在治疗方法。

更新日期:2020-05-06
down
wechat
bug