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Pain Modulation in WAG/Rij Epileptic Rats (A Genetic Model of Absence Epilepsy): Effects of Biological and Pharmacological Histone Deacetylase Inhibitors

Epigenetic mechanisms are involved in epilepsy and chronic pain development. About that, we studied the effects of the natural histone deacetylase (HDAC) inhibitor sodium butyrate (BUT) in comparison with valproic acid (VPA) in a validated genetic model of generalized absence epilepsy and epileptoge...

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Autores principales: De Caro, Carmen, Di Cesare Mannelli, Lorenzo, Branca, Jacopo Junio Valerio, Micheli, Laura, Citraro, Rita, Russo, Emilio, De Sarro, Giovambattista, Ghelardini, Carla, Calignano, Antonio, Russo, Roberto
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7745735/
https://www.ncbi.nlm.nih.gov/pubmed/33343343
http://dx.doi.org/10.3389/fphar.2020.549191
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author De Caro, Carmen
Di Cesare Mannelli, Lorenzo
Branca, Jacopo Junio Valerio
Micheli, Laura
Citraro, Rita
Russo, Emilio
De Sarro, Giovambattista
Ghelardini, Carla
Calignano, Antonio
Russo, Roberto
author_facet De Caro, Carmen
Di Cesare Mannelli, Lorenzo
Branca, Jacopo Junio Valerio
Micheli, Laura
Citraro, Rita
Russo, Emilio
De Sarro, Giovambattista
Ghelardini, Carla
Calignano, Antonio
Russo, Roberto
author_sort De Caro, Carmen
collection PubMed
description Epigenetic mechanisms are involved in epilepsy and chronic pain development. About that, we studied the effects of the natural histone deacetylase (HDAC) inhibitor sodium butyrate (BUT) in comparison with valproic acid (VPA) in a validated genetic model of generalized absence epilepsy and epileptogenesis. WAG/Rij rats were treated with BUT (30 mg/kg), VPA (300 mg/kg), and their combination (BUT + VPA) daily per os for 6 months. Rats were subjected at Randall–Selitto, von Frey, hot plate, and tail flick tests after 1, 3, and 6 months of treatment to evaluate hypersensitivity to noxious and non-noxiuous stimuli. Moreover, PPAR-γ (G3335 1 mg/kg), GABA-B (CGP35348 80 mg/kg), and opioid (naloxone 1 mg/kg) receptor antagonists were administrated to investigate the possible mechanisms involved in analgesic activity. The expression of NFkB, glutathione reductase, and protein oxidation (carbonylation) was also evaluated by Western blot analysis. WAG/Rij rats showed an altered pain threshold throughout the study (p < 0.001). BUT and BUT + VPA treatment reduced hypersensitivity (p < 0.01). VPA was significantly effective only after 1 month (p < 0.01). All the three receptors are involved in BUT + VPA effects (p < 0.001). BUT and BUT + VPA decreased the expression of NFkB and enhanced glutathione reductase (p < 0.01); protein oxidation (carbonylation) was reduced (p < 0.01). No effect was reported with VPA. In conclusion BUT, alone or in coadministration with VPA, is a valuable candidate for managing the epilepsy-related persistent pain.
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spelling pubmed-77457352020-12-18 Pain Modulation in WAG/Rij Epileptic Rats (A Genetic Model of Absence Epilepsy): Effects of Biological and Pharmacological Histone Deacetylase Inhibitors De Caro, Carmen Di Cesare Mannelli, Lorenzo Branca, Jacopo Junio Valerio Micheli, Laura Citraro, Rita Russo, Emilio De Sarro, Giovambattista Ghelardini, Carla Calignano, Antonio Russo, Roberto Front Pharmacol Pharmacology Epigenetic mechanisms are involved in epilepsy and chronic pain development. About that, we studied the effects of the natural histone deacetylase (HDAC) inhibitor sodium butyrate (BUT) in comparison with valproic acid (VPA) in a validated genetic model of generalized absence epilepsy and epileptogenesis. WAG/Rij rats were treated with BUT (30 mg/kg), VPA (300 mg/kg), and their combination (BUT + VPA) daily per os for 6 months. Rats were subjected at Randall–Selitto, von Frey, hot plate, and tail flick tests after 1, 3, and 6 months of treatment to evaluate hypersensitivity to noxious and non-noxiuous stimuli. Moreover, PPAR-γ (G3335 1 mg/kg), GABA-B (CGP35348 80 mg/kg), and opioid (naloxone 1 mg/kg) receptor antagonists were administrated to investigate the possible mechanisms involved in analgesic activity. The expression of NFkB, glutathione reductase, and protein oxidation (carbonylation) was also evaluated by Western blot analysis. WAG/Rij rats showed an altered pain threshold throughout the study (p < 0.001). BUT and BUT + VPA treatment reduced hypersensitivity (p < 0.01). VPA was significantly effective only after 1 month (p < 0.01). All the three receptors are involved in BUT + VPA effects (p < 0.001). BUT and BUT + VPA decreased the expression of NFkB and enhanced glutathione reductase (p < 0.01); protein oxidation (carbonylation) was reduced (p < 0.01). No effect was reported with VPA. In conclusion BUT, alone or in coadministration with VPA, is a valuable candidate for managing the epilepsy-related persistent pain. Frontiers Media S.A. 2020-12-03 /pmc/articles/PMC7745735/ /pubmed/33343343 http://dx.doi.org/10.3389/fphar.2020.549191 Text en Copyright © 2020 De Caro, Di Cesare Mannelli, Branca, Micheli, Citraro, Russo, De Sarro, Ghelardini, Calignano and Russo http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
De Caro, Carmen
Di Cesare Mannelli, Lorenzo
Branca, Jacopo Junio Valerio
Micheli, Laura
Citraro, Rita
Russo, Emilio
De Sarro, Giovambattista
Ghelardini, Carla
Calignano, Antonio
Russo, Roberto
Pain Modulation in WAG/Rij Epileptic Rats (A Genetic Model of Absence Epilepsy): Effects of Biological and Pharmacological Histone Deacetylase Inhibitors
title Pain Modulation in WAG/Rij Epileptic Rats (A Genetic Model of Absence Epilepsy): Effects of Biological and Pharmacological Histone Deacetylase Inhibitors
title_full Pain Modulation in WAG/Rij Epileptic Rats (A Genetic Model of Absence Epilepsy): Effects of Biological and Pharmacological Histone Deacetylase Inhibitors
title_fullStr Pain Modulation in WAG/Rij Epileptic Rats (A Genetic Model of Absence Epilepsy): Effects of Biological and Pharmacological Histone Deacetylase Inhibitors
title_full_unstemmed Pain Modulation in WAG/Rij Epileptic Rats (A Genetic Model of Absence Epilepsy): Effects of Biological and Pharmacological Histone Deacetylase Inhibitors
title_short Pain Modulation in WAG/Rij Epileptic Rats (A Genetic Model of Absence Epilepsy): Effects of Biological and Pharmacological Histone Deacetylase Inhibitors
title_sort pain modulation in wag/rij epileptic rats (a genetic model of absence epilepsy): effects of biological and pharmacological histone deacetylase inhibitors
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7745735/
https://www.ncbi.nlm.nih.gov/pubmed/33343343
http://dx.doi.org/10.3389/fphar.2020.549191
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