AI Article Synopsis
- Focal cortical dysplasia (FCD) is a key cause of hard-to-treat epilepsy, and this study explored how glucose metabolism is affected in different FCD types by studying GLUT1 expression and DNA methylation changes.
- Researchers found that hypermethylation of glucose-regulating genes can differentiate FCD subtypes from other conditions and that lower GLUT1 levels are linked to increased levels of VEGFα and MCT2.
- Decitabine treatment showed potential to restore glucose uptake and alter gene expression related to metabolism in brain cells, suggesting new pathways for developing biomarkers and early treatment strategies for FCD.
Article Abstract
Focal cortical dysplasia (FCD) is recognized as a significant etiological factor in pharmacoresistant intractable 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 (paired with matching blood) was assessed for DNA methylation changes of glucose metabolism-related genes. We evaluated GLUT1, VEGFα, MCT2, and mTOR expression by western blot analysis, 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 mMCD, MOGHE and non-lesional types in brain. 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 HEK cells. We demonstrated: 1) hypermethylation of glucose regulatory genes distinguish FCDIIa/b from mMCD, MOGHE and non-lesional types, 2) glucose uptake reduction is due to GLUT1 suppression mediated possibly by a GLUT1-mTOR mechanism; and 3) DNA methylation regulates cellular glucose update and metabolism. Together, these studies may lead to GLUT1-mediated biomarkers, glucose metabolism and identify early intervention strategies in FCD.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11527251 | PMC |
| http://dx.doi.org/10.21203/rs.3.rs-4946501/v1 | DOI Listing |
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