Sarcosine Suppresses Epileptogenesis in Rats With Effects on Hippocampal DNA Methylation

Abstract

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.

Cytosolic serine hydroxymethyltransferase controls lung adenocarcinoma cells migratory ability by modulating AMP kinase activity

“…1A ). The intracellular level of these amino acids was varied by increasing their concentration in the medium or by reducing their uptake by employing 4-Fluorophenyl-L-glycine (4LFPG) and sarcosine (SARC), which inhibit serine and glycine importers SLC1A4/SLC1A5 and GlyT1, respectively 15 , 16 . Using these inhibitors, we observed a reduction of the intracellular content of serine and glycine of about 18% for 4LFPG and 40% for SARC (Supplementary Fig.…”

Genomic and Metabolomic Landscape of Right-Sided and Left-Sided Colorectal Cancer: Potential Preventive Biomarkers

“…The higher level of the presumed sarcosine signal observed for LCRC (compared with that noted for RCRC) warrants further investigation. Sarcosine has recently been implicated in the methylation of genes associated with several diseases, including CRC [37][38][39]. In one study, the incubation of prostate cells with sarcosine stimulated DNA methyltransferases (DNMTs), resulting in increases in global DNA methylation [37].…”

Multi‐omic strategies applied to the study of pharmacoresistance in mesial temporal lobe epilepsy

“…Based on these results, the authors suggested that by acting in the demethylation pathway, sarcosine could attenuate the progression of epilepsy. 150 DNMTs also play a crucial role in DNA methylation, and changes in these enzymes have been observed in tissue from patients with MTLE. [151][152][153] However, to our knowledge, there is no published study in which the authors aimed to investigate the pharmacologic response of the DNMT inhibitors and their possible relationship to pharmacoresistance in patients with MTLE.…”

“…Moreover, TET1 expression was upregulated. Based on these results, the authors suggested that by acting in the demethylation pathway, sarcosine could attenuate the progression of epilepsy 150 …”

“…Sarcosine (also known as N ‐methylglycine) is another potential ASM; it plays a role in balancing methyl radicals in the transmethylation process. 149 Shen et al 150 recently investigated the role of sarcosine treatment in a rat kindling model. DNA methylation was evaluated in the 5mC and 5hmC contexts via immunohistochemistry.…”