Sarcosine Suppresses Epileptogenesis in Rats With Effects on Hippocampal DNA Methylation.
Hai-Ying Shen,Landen Weltha,John M Cook,Raey Gesese,Wakaba Omi,Sadie B Baer,Rizelle Mae Rose,Jesica Reemmer,Detlev Boison +8 more
TL;DR: It is suggested that sarcosine has unprecedented disease-modifying properties in a kindling model of epileptogenesis in rats, which was associated with altered hippocampal DNA methylation, and manipulation of the glycine system is a potential therapeutic approach to attenuate the development of epilepsy.
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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.
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Citations
Multi-omic strategies applied to the study of pharmacoresistance in mesial temporal lobe epilepsy.
Estela M. Bruxel,Amanda Morato do Canto,Danielle do Carmo Ferreira Bruno,Jaqueline C Geraldis,Iscia Lopes-Cendes +4 more
- 06 Sep 2021
TL;DR: In this paper, the authors present and discuss the contribution of different omic modalities to understand the basic mechanisms determining pharmacoresistance in patients with mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE+HS).
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Assay for TET1 activity and its inhibitors screening with signal amplification by both nanoparticles and Ru(III) redox recycling.
TL;DR: In this paper, a novel biosensor was constructed for TET1 detection and its inhibitors screening utilizing restriction digestion of endonuclease enzyme MspI, which plays a key role in dynamic DNA methylation-demethylation process.
8
Aerobic exercise alters DNA hydroxymethylation levels in an experimental rodent model of temporal lobe epilepsy
Silvienne C Sint Jago,Rudhab Bahabry,Anna Maria Schreiber,Julia Homola,Tram Ngyuen,Fernando Meijia,Jane B. Allendorfer,Farah D. Lubin +7 more
- 01 Dec 2023
TL;DR: Chronic aerobic exercise decreases serum BDNF and increases serum IL-6 levels and TET1 emerges as the central enzyme affected by chronic aerobic exercise in TLE, indicating exercise-driven DNA 5-hmC changes in TLE are neuron-specific.
1
Cytosolic serine hydroxymethyltransferase controls lung adenocarcinoma cells migratory ability by modulating AMP kinase activity.
Amani Bouzidi,Maria Chiara Magnifico,Maria Chiara Magnifico,Alessandro Paiardini,Alberto Macone,Giovanna Boumis,Giorgio Giardina,Serena Rinaldo,Francesca Romana Liberati,Clotilde Lauro,Cristina Limatola,Chiara Lanzillotta,Antonella Tramutola,Marzia Perluigi,Gianluca Sgarbi,Giancarlo Solaini,Alessandra Baracca,Alessio Paone,Francesca Cutruzzolà +18 more
TL;DR: It is demonstrated that cytosolic serine metabolism plays a key role in controlling motility, suggesting that cells are able to dynamically exploit the compartmentalization of this metabolism to adapt their metabolic needs to different cell functions (movement vs. proliferation).
Alterations in DNA 5-hydroxymethylation patterns in the hippocampus of an experimental model of chronic epilepsy
Rudhab Bahabry,Rebecca M. Hauser,Richard G. Sánchez Silvienne,Sint Jago,Lara Ianov,Remy J. Stuckey,R. R. Parrish,Lawrence Ver Hoef,Farah D. Lubin,Silvienne Sint,BS Jago +10 more
Abstract: Temporal lobe epilepsy (TLE) is a type of focal epilepsy characterized by spontaneous recurrent seizures originating from the hippocampus. The epigenetic reprogramming hypothesis of epileptogenesis suggests that the development of TLE is associated with alterations in gene transcription changes resulting in a hyperexcitable network in TLE. DNA 5-methylcytosine (5-mC) is an epigenetic mechanism that has been associated with chronic epilepsy. However, the contribution of 5-hydroxymethylcytosine (5-hmC), a product of 5-mC demethylation by the Ten-Eleven Translocation (TET) family proteins in chronic TLE is poorly understood. 5-hmC is abundant in the brain and acts as a stable epigenetic mark altering gene expression through several mechanisms. Here, we found that the levels of bulk DNA 5-hmC but not 5-mC were significantly reduced in the hippocampus of human TLE patients and in the kainic acid (KA) TLE rat model. Using 5-hmC hMeDIP-sequencing, we characterized 5-hmC distribution across the genome and found bidirectional regulation of 5-hmC at intergenic regions within gene bodies. We found that hypohydroxymethylated 5-hmC intergenic regions were associated with several epilepsy-related genes, including Gal, SV2, and Kcnj11 and hyperdroxymethylation 5-hmC intergenic regions were associated with Gad65, TLR4, and Bdnf gene expression. Mechanistically, Tet1 knockdown in the hippocampus was sufficient to decrease 5-hmC levels and increase seizure susceptibility following KA administration. In contrast, Tet1 overexpression in the hippocampus resulted in increased 5-hmC levels associated with improved seizure resiliency in response to KA. These findings suggest an important role for 5-hmC as an epigenetic regulator of epilepsy that can be manipulated to influence seizure outcomes.
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Asla Pitkänen,Katarzyna Lukasiuk +1 more
TL;DR: In this paper, molecular profiling studies have provided an insight into molecular changes that contribute to formation of ictogenic neuronal networks, including genes regulating synaptic or neuronal plasticity, cell death, proliferation, and inflammatory or immune responses.
Epileptogenesis in the immature brain: emerging mechanisms
TL;DR: The factors responsible for enhanced seizure susceptibility in the developing brain are reviewed, and age-specific mechanisms of epileptogenesis are considered, to provide biomarkers for identifying patients at risk of developing epilepsy or for monitoring disease progression.
Mechanisms of epileptogenesis: a convergence on neural circuit dysfunction
TL;DR: It is suggested that insights into the mechanisms of epileptogenesis converge at the level of cortical circuit dysfunction, with the hope of preventing epilepsy before seizures emerge.
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