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Rapid Increases in proBDNF after Pilocarpine-Induced Status Epilepticus in Mice Are Associated with Reduced proBDNF Cleavage Machinery123

Brain-derived neurotrophic factor (BDNF) levels are elevated after status epilepticus (SE), leading to activation of multiple signaling pathways, including the janus kinase/signal transducer and activator of transcription pathway that mediates a decrease in GABA(A) receptor α1 subunits in the hippoc...

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Autores principales: Thomas, Ajay X., Cruz Del Angel, Yasmin, Gonzalez, Marco I., Carrel, Andrew J., Carlsen, Jessica, Lam, Philip M., Hempstead, Barbara L., Russek, Shelley. J., Brooks-Kayal, Amy R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Society for Neuroscience 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4814566/
https://www.ncbi.nlm.nih.gov/pubmed/27057559
http://dx.doi.org/10.1523/ENEURO.0020-15.2016
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author Thomas, Ajay X.
Cruz Del Angel, Yasmin
Gonzalez, Marco I.
Carrel, Andrew J.
Carlsen, Jessica
Lam, Philip M.
Hempstead, Barbara L.
Russek, Shelley. J.
Brooks-Kayal, Amy R.
author_facet Thomas, Ajay X.
Cruz Del Angel, Yasmin
Gonzalez, Marco I.
Carrel, Andrew J.
Carlsen, Jessica
Lam, Philip M.
Hempstead, Barbara L.
Russek, Shelley. J.
Brooks-Kayal, Amy R.
author_sort Thomas, Ajay X.
collection PubMed
description Brain-derived neurotrophic factor (BDNF) levels are elevated after status epilepticus (SE), leading to activation of multiple signaling pathways, including the janus kinase/signal transducer and activator of transcription pathway that mediates a decrease in GABA(A) receptor α1 subunits in the hippocampus (Lund et al., 2008). While BDNF can signal via its pro or mature form, the relative contribution of these forms to signaling after SE is not fully known. In the current study, we investigate changes in proBDNF levels acutely after SE in C57BL/6J mice. In contrast to previous reports (Unsain et al., 2008; Volosin et al., 2008; VonDran et al., 2014), our studies found that levels of proBDNF in the hippocampus are markedly elevated as early as 3 h after SE onset and remain elevated for 7 d. Immunohistochemistry studies indicate that seizure-induced BDNF localizes to all hippocampal subfields, predominantly in principal neurons and also in astrocytes. Analysis of the proteolytic machinery that cleaves proBDNF to produce mature BDNF demonstrates that acutely after SE there is a decrease in tissue plasminogen activator and an increase in plasminogen activator inhibitor-1 (PAI-1), an inhibitor of extracellular and intracellular cleavage, which normalizes over the first week after SE. In vitro treatment of hippocampal slices from animals 24 h after SE with a PAI-1 inhibitor reduces proBDNF levels. These findings suggest that rapid proBDNF increases following SE are due in part to reduced cleavage, and that proBDNF may be part of the initial neurotrophin response driving intracellular signaling during the acute phase of epileptogenesis.
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spelling pubmed-48145662016-04-07 Rapid Increases in proBDNF after Pilocarpine-Induced Status Epilepticus in Mice Are Associated with Reduced proBDNF Cleavage Machinery123 Thomas, Ajay X. Cruz Del Angel, Yasmin Gonzalez, Marco I. Carrel, Andrew J. Carlsen, Jessica Lam, Philip M. Hempstead, Barbara L. Russek, Shelley. J. Brooks-Kayal, Amy R. eNeuro New Research Brain-derived neurotrophic factor (BDNF) levels are elevated after status epilepticus (SE), leading to activation of multiple signaling pathways, including the janus kinase/signal transducer and activator of transcription pathway that mediates a decrease in GABA(A) receptor α1 subunits in the hippocampus (Lund et al., 2008). While BDNF can signal via its pro or mature form, the relative contribution of these forms to signaling after SE is not fully known. In the current study, we investigate changes in proBDNF levels acutely after SE in C57BL/6J mice. In contrast to previous reports (Unsain et al., 2008; Volosin et al., 2008; VonDran et al., 2014), our studies found that levels of proBDNF in the hippocampus are markedly elevated as early as 3 h after SE onset and remain elevated for 7 d. Immunohistochemistry studies indicate that seizure-induced BDNF localizes to all hippocampal subfields, predominantly in principal neurons and also in astrocytes. Analysis of the proteolytic machinery that cleaves proBDNF to produce mature BDNF demonstrates that acutely after SE there is a decrease in tissue plasminogen activator and an increase in plasminogen activator inhibitor-1 (PAI-1), an inhibitor of extracellular and intracellular cleavage, which normalizes over the first week after SE. In vitro treatment of hippocampal slices from animals 24 h after SE with a PAI-1 inhibitor reduces proBDNF levels. These findings suggest that rapid proBDNF increases following SE are due in part to reduced cleavage, and that proBDNF may be part of the initial neurotrophin response driving intracellular signaling during the acute phase of epileptogenesis. Society for Neuroscience 2016-03-30 /pmc/articles/PMC4814566/ /pubmed/27057559 http://dx.doi.org/10.1523/ENEURO.0020-15.2016 Text en Copyright © 2016 Thomas et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
spellingShingle New Research
Thomas, Ajay X.
Cruz Del Angel, Yasmin
Gonzalez, Marco I.
Carrel, Andrew J.
Carlsen, Jessica
Lam, Philip M.
Hempstead, Barbara L.
Russek, Shelley. J.
Brooks-Kayal, Amy R.
Rapid Increases in proBDNF after Pilocarpine-Induced Status Epilepticus in Mice Are Associated with Reduced proBDNF Cleavage Machinery123
title Rapid Increases in proBDNF after Pilocarpine-Induced Status Epilepticus in Mice Are Associated with Reduced proBDNF Cleavage Machinery123
title_full Rapid Increases in proBDNF after Pilocarpine-Induced Status Epilepticus in Mice Are Associated with Reduced proBDNF Cleavage Machinery123
title_fullStr Rapid Increases in proBDNF after Pilocarpine-Induced Status Epilepticus in Mice Are Associated with Reduced proBDNF Cleavage Machinery123
title_full_unstemmed Rapid Increases in proBDNF after Pilocarpine-Induced Status Epilepticus in Mice Are Associated with Reduced proBDNF Cleavage Machinery123
title_short Rapid Increases in proBDNF after Pilocarpine-Induced Status Epilepticus in Mice Are Associated with Reduced proBDNF Cleavage Machinery123
title_sort rapid increases in probdnf after pilocarpine-induced status epilepticus in mice are associated with reduced probdnf cleavage machinery123
topic New Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4814566/
https://www.ncbi.nlm.nih.gov/pubmed/27057559
http://dx.doi.org/10.1523/ENEURO.0020-15.2016
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