Persistent DNA methylation and down-regulation of homeostatic genes in astrocytes after pilocarpine-induced status epilepticus: implications for epileptogenesis

Epilepsy is a debilitating neurological disorder characterized by recurrent seizures, affecting millions of patients worldwide. Retrospective studies in temporal lobe epilepsy (TLE) patients have shown a high incidence of an initial precipitating event (IPE) in early childhood, followed by a silent...

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Autores principales: Gómez Cuautle, Dante, Rossi, Alicia, Márquez Cadena, Milton Paul, Villarrea, Alejandro, D'Alessio, Luciana, Alberto Javier, Ramos
Formato: Artículo de publicación periódica
Lenguaje:Inglés
Publicado: Clinical Science. Portland Press Ltd. 2026
Materias:
ASTROCYTES, EPIGENETICS, EPILEPSY, HOMEOSTASIS
Acceso en línea:https://hdl.handle.net/20.500.14769/5417
https://doi.org/10.1042/CS20256367
Aporte de:
Repositorio Institucional Instituto Tecnológico de Buenos Aires (ITBA) de Instituto Tecnológico de Buenos Aires (ITBA)
id I32-R138-20.500.14769-5417
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spelling I32-R138-20.500.14769-54172026-04-16T18:04:20Z Persistent DNA methylation and down-regulation of homeostatic genes in astrocytes after pilocarpine-induced status epilepticus: implications for epileptogenesis Gómez Cuautle, Dante Rossi, Alicia Márquez Cadena, Milton Paul Villarrea, Alejandro D'Alessio, Luciana Alberto Javier, Ramos ASTROCYTES, EPIGENETICS, EPILEPSY, HOMEOSTASIS Epilepsy is a debilitating neurological disorder characterized by recurrent seizures, affecting millions of patients worldwide. Retrospective studies in temporal lobe epilepsy (TLE) patients have shown a high incidence of an initial precipitating event (IPE) in early childhood, followed by a silent period where epileptogenesis occurs to end up in chronic epilepsy. Epileptogenesis, the process through which a normal brain undergoes structural and functional changes leading to epilepsy, is not completely understood. We hypothesized that epigenetics may be involved in epileptogenesis, specifically affecting astrocytes through pathological remodeling. To study this process, we used three approaches: the lithium–pilocarpine model of TLE in rats, primary astroglial cultures exposed to epileptogenic DAMP named HMGB1, and brain tissue samples resected from TLE patients with drug-resistant epilepsy. We found that the IPE achieved by lithium–pilocarpine treatment (127/30 mg/kg IP) induced the DNA methylation of astrocytes at 7-, 21-, and 35-days post-IPE, indicating persistent epigenetic alterations in astrocytes during the epileptogenic period. In addition, we observed the down-regulation of homeostatic astroglial genes, including AQP4, glutamine synthase (GS), and Kir4.1, along with increased expression of proinflammatory genes (C3, MAFG) and DNA methyltransferases (DNMT). These alterations were mimicked in primary astrocyte cultures exposed to the epileptogenic HMGB1 (500 ng/ml; 18 h), which resulted in the hypermethylation of homeostatic astroglial genes and repression of homeostatic genes. HMGB1-induced repression of astroglial homeostatic genes was prevented by the treatment with DNMT inhibitor decitabine. Interestingly, astrocytes from TLE patients brains showed reactive astrogliosis, increased DNA methylation, and down-regulation of homeostatic genes Kir4.1 and GS. Taken together, these findings show that astrocytes are pathologically altered during the epileptogenic period by epigenetic modifications, combining the proinflammatory gain of function with the loss of homeostatic profile. This may contribute to the long-term alterations underlying epileptogenesis. 2026-04-16T18:04:19Z 2026-04-16T18:04:19Z 2026-02-11 Artículo de publicación periódica Persistent DNA methylation and down-regulation of astroglial genes following status epilepticus. Clinical Science, 140(2), 221. https://doi.org/10.1042/CS20256367 1470-8736 https://hdl.handle.net/20.500.14769/5417 https://doi.org/10.1042/CS20256367 en Clinical Science. Portland Press Ltd.
institution Instituto Tecnológico de Buenos Aires (ITBA)
institution_str I-32
repository_str R-138
collection Repositorio Institucional Instituto Tecnológico de Buenos Aires (ITBA)
language Inglés
topic ASTROCYTES, EPIGENETICS, EPILEPSY, HOMEOSTASIS
spellingShingle ASTROCYTES, EPIGENETICS, EPILEPSY, HOMEOSTASIS
Gómez Cuautle, Dante
Rossi, Alicia
Márquez Cadena, Milton Paul
Villarrea, Alejandro
D'Alessio, Luciana
Alberto Javier, Ramos
Persistent DNA methylation and down-regulation of homeostatic genes in astrocytes after pilocarpine-induced status epilepticus: implications for epileptogenesis
topic_facet ASTROCYTES, EPIGENETICS, EPILEPSY, HOMEOSTASIS
description Epilepsy is a debilitating neurological disorder characterized by recurrent seizures, affecting millions of patients worldwide. Retrospective studies in temporal lobe epilepsy (TLE) patients have shown a high incidence of an initial precipitating event (IPE) in early childhood, followed by a silent period where epileptogenesis occurs to end up in chronic epilepsy. Epileptogenesis, the process through which a normal brain undergoes structural and functional changes leading to epilepsy, is not completely understood. We hypothesized that epigenetics may be involved in epileptogenesis, specifically affecting astrocytes through pathological remodeling. To study this process, we used three approaches: the lithium–pilocarpine model of TLE in rats, primary astroglial cultures exposed to epileptogenic DAMP named HMGB1, and brain tissue samples resected from TLE patients with drug-resistant epilepsy. We found that the IPE achieved by lithium–pilocarpine treatment (127/30 mg/kg IP) induced the DNA methylation of astrocytes at 7-, 21-, and 35-days post-IPE, indicating persistent epigenetic alterations in astrocytes during the epileptogenic period. In addition, we observed the down-regulation of homeostatic astroglial genes, including AQP4, glutamine synthase (GS), and Kir4.1, along with increased expression of proinflammatory genes (C3, MAFG) and DNA methyltransferases (DNMT). These alterations were mimicked in primary astrocyte cultures exposed to the epileptogenic HMGB1 (500 ng/ml; 18 h), which resulted in the hypermethylation of homeostatic astroglial genes and repression of homeostatic genes. HMGB1-induced repression of astroglial homeostatic genes was prevented by the treatment with DNMT inhibitor decitabine. Interestingly, astrocytes from TLE patients brains showed reactive astrogliosis, increased DNA methylation, and down-regulation of homeostatic genes Kir4.1 and GS. Taken together, these findings show that astrocytes are pathologically altered during the epileptogenic period by epigenetic modifications, combining the proinflammatory gain of function with the loss of homeostatic profile. This may contribute to the long-term alterations underlying epileptogenesis.
format Artículo de publicación periódica
author Gómez Cuautle, Dante
Rossi, Alicia
Márquez Cadena, Milton Paul
Villarrea, Alejandro
D'Alessio, Luciana
Alberto Javier, Ramos
author_facet Gómez Cuautle, Dante
Rossi, Alicia
Márquez Cadena, Milton Paul
Villarrea, Alejandro
D'Alessio, Luciana
Alberto Javier, Ramos
author_sort Gómez Cuautle, Dante
title Persistent DNA methylation and down-regulation of homeostatic genes in astrocytes after pilocarpine-induced status epilepticus: implications for epileptogenesis
title_short Persistent DNA methylation and down-regulation of homeostatic genes in astrocytes after pilocarpine-induced status epilepticus: implications for epileptogenesis
title_full Persistent DNA methylation and down-regulation of homeostatic genes in astrocytes after pilocarpine-induced status epilepticus: implications for epileptogenesis
title_fullStr Persistent DNA methylation and down-regulation of homeostatic genes in astrocytes after pilocarpine-induced status epilepticus: implications for epileptogenesis
title_full_unstemmed Persistent DNA methylation and down-regulation of homeostatic genes in astrocytes after pilocarpine-induced status epilepticus: implications for epileptogenesis
title_sort persistent dna methylation and down-regulation of homeostatic genes in astrocytes after pilocarpine-induced status epilepticus: implications for epileptogenesis
publisher Clinical Science. Portland Press Ltd.
publishDate 2026
url https://hdl.handle.net/20.500.14769/5417
https://doi.org/10.1042/CS20256367
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