Rapid Increases in proBDNF after Pilocarpine-Induced Status Epilepticus in Mice Are Associated with Reduced proBDNF Cleavage Machinery
| Autor: | Shelley J. Russek, Barbara L. Hempstead, Yasmin Cruz Del Angel, Ajay X. Thomas, Amy R. Brooks-Kayal, Philip M. Lam, Jessica Carlsen, Andrew J. Carrel, Marco I. González |
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| Rok vydání: | 2015 |
| Předmět: |
Male
medicine.medical_specialty PAI-1 Hippocampal formation Hippocampus 03 medical and health sciences chemistry.chemical_compound Mice 0302 clinical medicine Status Epilepticus Neurotrophic factors Internal medicine Plasminogen Activator Inhibitor 1 ProBDNF medicine Animals tPA cleavage Protein Precursors 030304 developmental biology Brain-derived neurotrophic factor Neurons 0303 health sciences biology General Neuroscience Brain-Derived Neurotrophic Factor Pilocarpine General Medicine New Research Mice Inbred C57BL Endocrinology BDNF chemistry nervous system Plasminogen activator inhibitor-1 Astrocytes STAT protein biology.protein epilepsy Disorders of the Nervous System Signal transduction Plasminogen activator Protein Processing Post-Translational 030217 neurology & neurosurgery Neurotrophin |
| Zdroj: | eNeuro |
| ISSN: | 2373-2822 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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