Sarcosine Suppresses Epileptogenesis in Rats With Effects on Hippocampal DNA Methylation.
DNA methylation
DNMT
GlyT1 inhibition
TET1
dentate gyrus
epileptogenesis
sarcosine
Journal
Frontiers in molecular neuroscience
ISSN: 1662-5099
Titre abrégé: Front Mol Neurosci
Pays: Switzerland
ID NLM: 101477914
Informations de publication
Date de publication:
2020
2020
Historique:
received:
06
03
2020
accepted:
06
05
2020
entrez:
26
6
2020
pubmed:
26
6
2020
medline:
26
6
2020
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 32581708
doi: 10.3389/fnmol.2020.00097
pmc: PMC7291815
doi:
Types de publication
Journal Article
Langues
eng
Pagination
97Subventions
Organisme : NINDS NIH HHS
ID : R01 NS084920
Pays : United States
Informations de copyright
Copyright © 2020 Shen, Weltha, Cook, Gesese, Omi, Baer, Rose, Reemmer and Boison.
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