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Beneficial Effect of Phenytoin and Carbamazepine on GFAP Gene Expression and Mutant GFAP Folding in a Cellular Model of Alexander’s Disease

Alexander’s disease (AxD) is a rare, usually relentlessly progressive disorder of astroglial cells in the central nervous system related to mutations in the gene encoding the type III intermediate filament protein, glial fibrillary acidic protein (GFAP). The pathophysiology of AxD is only partially...

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Autores principales: Bachetti, Tiziana, Zanni, Eleonora Di, Adamo, Annalisa, Rosamilia, Francesca, Sechi, M. Margherita, Solla, Paolo, Bozzo, Matteo, Ceccherini, Isabella, Sechi, GianPietro
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8688807/
https://www.ncbi.nlm.nih.gov/pubmed/34950024
http://dx.doi.org/10.3389/fphar.2021.723218
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author Bachetti, Tiziana
Zanni, Eleonora Di
Adamo, Annalisa
Rosamilia, Francesca
Sechi, M. Margherita
Solla, Paolo
Bozzo, Matteo
Ceccherini, Isabella
Sechi, GianPietro
author_facet Bachetti, Tiziana
Zanni, Eleonora Di
Adamo, Annalisa
Rosamilia, Francesca
Sechi, M. Margherita
Solla, Paolo
Bozzo, Matteo
Ceccherini, Isabella
Sechi, GianPietro
author_sort Bachetti, Tiziana
collection PubMed
description Alexander’s disease (AxD) is a rare, usually relentlessly progressive disorder of astroglial cells in the central nervous system related to mutations in the gene encoding the type III intermediate filament protein, glial fibrillary acidic protein (GFAP). The pathophysiology of AxD is only partially understood. Available data indicate that an excessive GFAP gene expression may play a role. In particular, a “threshold hypothesis” has been reported, suggesting that mutant GFAP representing about 20% of the total cellular GFAP should be sufficient to cause disease. Thus, strategies based on reducing cellular mutant GFAP protein levels and/or activating biological processes involved in the correct protein folding could be effective in counteracting the toxic effect of misfolded GFAP. Considering that clomipramine (CLM), which has been selected by a wide small molecules screening as the greatest inhibitory potential drug against GFAP expression, is contraindicated because of its proconvulsant activity in the infantile form of AxD, which is also characterized by the occurrence of epileptic seizures, two powerful antiepileptic agents, carbamazepine (CBZ) and phenytoin (PHT), which share specific stereochemical features in common with CLM, were taken into consideration in a reliable in vitro model of AxD. In the present work, we document for the first time that CBZ and PHT have a definite inhibitory effect on pathological GFAP cellular expression and folding. Moreover, we confirm previous results of a similar beneficial effect of CLM. In addition, we have demonstrated that CBZ and CLM play a refolding effect on mutant GFAP proteins, likely ascribed at the induction of CRYAB expression, resulting in the decrease of mutant GFAP aggregates formation. As CBZ and PHT are currently approved for use in humans, their documented effects on pathological GFAP cellular expression and folding may indicate a potential therapeutic role as disease-modifying agents of these drugs in the clinical management of AxD, particularly in AxD patients with focal epilepsy with and without secondary generalization.
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spelling pubmed-86888072021-12-22 Beneficial Effect of Phenytoin and Carbamazepine on GFAP Gene Expression and Mutant GFAP Folding in a Cellular Model of Alexander’s Disease Bachetti, Tiziana Zanni, Eleonora Di Adamo, Annalisa Rosamilia, Francesca Sechi, M. Margherita Solla, Paolo Bozzo, Matteo Ceccherini, Isabella Sechi, GianPietro Front Pharmacol Pharmacology Alexander’s disease (AxD) is a rare, usually relentlessly progressive disorder of astroglial cells in the central nervous system related to mutations in the gene encoding the type III intermediate filament protein, glial fibrillary acidic protein (GFAP). The pathophysiology of AxD is only partially understood. Available data indicate that an excessive GFAP gene expression may play a role. In particular, a “threshold hypothesis” has been reported, suggesting that mutant GFAP representing about 20% of the total cellular GFAP should be sufficient to cause disease. Thus, strategies based on reducing cellular mutant GFAP protein levels and/or activating biological processes involved in the correct protein folding could be effective in counteracting the toxic effect of misfolded GFAP. Considering that clomipramine (CLM), which has been selected by a wide small molecules screening as the greatest inhibitory potential drug against GFAP expression, is contraindicated because of its proconvulsant activity in the infantile form of AxD, which is also characterized by the occurrence of epileptic seizures, two powerful antiepileptic agents, carbamazepine (CBZ) and phenytoin (PHT), which share specific stereochemical features in common with CLM, were taken into consideration in a reliable in vitro model of AxD. In the present work, we document for the first time that CBZ and PHT have a definite inhibitory effect on pathological GFAP cellular expression and folding. Moreover, we confirm previous results of a similar beneficial effect of CLM. In addition, we have demonstrated that CBZ and CLM play a refolding effect on mutant GFAP proteins, likely ascribed at the induction of CRYAB expression, resulting in the decrease of mutant GFAP aggregates formation. As CBZ and PHT are currently approved for use in humans, their documented effects on pathological GFAP cellular expression and folding may indicate a potential therapeutic role as disease-modifying agents of these drugs in the clinical management of AxD, particularly in AxD patients with focal epilepsy with and without secondary generalization. Frontiers Media S.A. 2021-12-07 /pmc/articles/PMC8688807/ /pubmed/34950024 http://dx.doi.org/10.3389/fphar.2021.723218 Text en Copyright © 2021 Bachetti, Zanni, Adamo, Rosamilia, Sechi, Solla, Bozzo, Ceccherini and Sechi. https://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
Bachetti, Tiziana
Zanni, Eleonora Di
Adamo, Annalisa
Rosamilia, Francesca
Sechi, M. Margherita
Solla, Paolo
Bozzo, Matteo
Ceccherini, Isabella
Sechi, GianPietro
Beneficial Effect of Phenytoin and Carbamazepine on GFAP Gene Expression and Mutant GFAP Folding in a Cellular Model of Alexander’s Disease
title Beneficial Effect of Phenytoin and Carbamazepine on GFAP Gene Expression and Mutant GFAP Folding in a Cellular Model of Alexander’s Disease
title_full Beneficial Effect of Phenytoin and Carbamazepine on GFAP Gene Expression and Mutant GFAP Folding in a Cellular Model of Alexander’s Disease
title_fullStr Beneficial Effect of Phenytoin and Carbamazepine on GFAP Gene Expression and Mutant GFAP Folding in a Cellular Model of Alexander’s Disease
title_full_unstemmed Beneficial Effect of Phenytoin and Carbamazepine on GFAP Gene Expression and Mutant GFAP Folding in a Cellular Model of Alexander’s Disease
title_short Beneficial Effect of Phenytoin and Carbamazepine on GFAP Gene Expression and Mutant GFAP Folding in a Cellular Model of Alexander’s Disease
title_sort beneficial effect of phenytoin and carbamazepine on gfap gene expression and mutant gfap folding in a cellular model of alexander’s disease
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8688807/
https://www.ncbi.nlm.nih.gov/pubmed/34950024
http://dx.doi.org/10.3389/fphar.2021.723218
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