Ghosh Chaitali, Westcott Rosemary, Skvasik David, Khurana Ishant, Khoury Jean, Blumcke Ingmar, El-Osta Assam, Najm Imad M
Neurovascular Research, Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH, 44195, USA.
Department of Biomedical Engineering and Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH, USA.
Mol Neurobiol. 2025 Apr 7. doi: 10.1007/s12035-025-04871-z.
Focal cortical dysplasia (FCD) is a significant etiological factor in drug-resistant epilepsy, linked with disturbances in neurovascular metabolism. Our study investigated regulation of glucose-transporter1 (GLUT1) and cerebral hypometabolism within FCD subtypes. Surgically excised human brain specimens underwent histopathological categorization. A subset of samples was assessed for DNA methylation changes of glucose metabolism-related genes. We evaluated GLUT1, vascular endothelial growth factor alpha (VEGFα), monocarboxylate-transporter (MCT2), and mammalian target of rapamycin (mTOR) expression, measured glucose-lactate concentrations, and established correlations with patients' demographic and clinical profiles. Furthermore, we investigated the impact of DNA methylation inhibitor decitabine and hypometabolic condition on the uptake of [H]-2-deoxyglucose and ATPase in epileptic-brain endothelial cells (EPI-EC). We observed hypermethylation of GLUT1 and glucose metabolic genes in FCD brain/blood samples and could distinguish FCDIIa/b from mild malformations of cortical development (mMCD), with oligodendroglial hyperplasia (MOGHE) and non-lesional brains. Low GLUT1 and glucose-lactate ratios corresponded to elevated VEGFα and MCT2 in FCDIIa/b vs. non-lesional tissues, independent of age, gender, seizure-onset, or duration of epilepsy. Increased mTOR-signaling in FCDIIa/b tissues was evident. Decitabine stimulation increased GLUT1, decreased VEGFα expression, restored glucose uptake and ATPase activity in EPI-ECs, and reduced mTOR and MCT2 levels in human embryonic-kidney cells. We demonstrated: hypermethylation of glucose regulatory genes distinguish FCDIIa/b from mMCD, MOGHE and non-lesional types, glucose uptake reduction is due to GLUT1 suppression mediated possibly by a GLUT1-mTOR mechanism; and DNA methylation regulates cellular glucose uptake and metabolism. Together, these studies may lead to GLUT1-mediated biomarkers and identify early intervention strategies in FCD.
局灶性皮质发育不良（FCD）是耐药性癫痫的一个重要病因，与神经血管代谢紊乱有关。我们的研究调查了FCD亚型中葡萄糖转运蛋白1（GLUT1）的调节和脑代谢减退情况。对手术切除的人脑标本进行组织病理学分类。对一部分样本评估葡萄糖代谢相关基因的DNA甲基化变化。我们评估了GLUT1、血管内皮生长因子α（VEGFα）、单羧酸转运蛋白（MCT2）和雷帕霉素靶蛋白（mTOR）的表达，测量了葡萄糖-乳酸浓度，并与患者的人口统计学和临床特征建立相关性。此外，我们研究了DNA甲基化抑制剂地西他滨和代谢减退条件对癫痫脑内皮细胞（EPI-EC）中[H]-2-脱氧葡萄糖摄取和ATP酶的影响。我们观察到FCD脑/血样本中GLUT1和葡萄糖代谢基因的高甲基化，并且能够将FCDIIa/b与皮质发育轻度畸形（mMCD）、少突胶质细胞增生（MOGHE）和无病变脑区分开来。与无病变组织相比，FCDIIa/b中低GLUT1和葡萄糖-乳酸比值对应于VEGFα和MCT2升高，与年龄、性别、癫痫发作起始或癫痫持续时间无关。FCDIIa/b组织中mTOR信号明显增加。地西他滨刺激增加了GLUT1，降低了VEGFα表达，恢复了EPI-EC中的葡萄糖摄取和ATP酶活性，并降低了人胚肾细胞中的mTOR和MCT2水平。我们证明：葡萄糖调节基因的高甲基化将FCDIIa/b与mMCD、MOGHE和无病变类型区分开来，葡萄糖摄取减少是由于可能由GLUT1-mTOR机制介导的GLUT1抑制；并且DNA甲基化调节细胞葡萄糖摄取和代谢。总之，这些研究可能会产生GLUT1介导的生物标志物，并确定FCD的早期干预策略。
