The glucocorticoid receptor specific modulator CORT108297 reduces brain pathology following status epilepticus
| Autor: | Venkat Suru, Steve C. Danzer, Kimberly L. Kraus, Kevin D. Gaitonde, Benjamin A. Packard, Aynara C. Wulsin, Salwa R. Arafa, James P. Herman |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Male Pathology medicine.medical_specialty Status epilepticus Heterocyclic Compounds 4 or More Rings Hippocampus Article 03 medical and health sciences chemistry.chemical_compound Mice 0302 clinical medicine Glucocorticoid receptor Receptors Glucocorticoid Status Epilepticus Developmental Neuroscience Corticosterone medicine Animals Aza Compounds Dose-Response Relationship Drug business.industry Pilocarpine Granule cell 030104 developmental biology medicine.anatomical_structure Glucocorticoid secretion Neurology chemistry medicine.symptom business 030217 neurology & neurosurgery Hypothalamic–pituitary–adrenal axis Glucocorticoid Astrocyte medicine.drug |
| Zdroj: | Exp Neurol |
| Popis: | Objective Glucocorticoid levels rise rapidly following status epilepticus and remain elevated for weeks after the injury. To determine whether glucocorticoid receptor activation contributes to the pathological sequelae of status epilepticus, mice were treated with a novel glucocorticoid receptor modulator, C108297. Methods Mice were treated with either C108297 or vehicle for 10 days beginning one day after pilocarpine-induced status epilepticus. Baseline and stress-induced glucocorticoid secretion were assessed to determine whether hypothalamic-pituitary-adrenal axis hyperreactivity could be controlled. Status epilepticus-induced pathology was assessed by quantifying ectopic hippocampal granule cell density, microglial density, astrocyte density and mossy cell loss. Neuronal network function was examined indirectly by determining the density of Fos immunoreactive neurons following restraint stress. Results Treatment with C108297 attenuated corticosterone hypersecretion after status epilepticus. Treatment also decreased the density of hilar ectopic granule cells and reduced microglial proliferation. Mossy cell loss, on the other hand, was not prevented in treated mice. C108297 altered the cellular distribution of Fos protein but did not restore the normal pattern of expression. Interpretation Results demonstrate that baseline corticosterone levels can be normalized with C108297, and implicate glucocorticoid signaling in the development of structural changes following status epilepticus. These findings support the further development of glucocorticoid receptor modulators as novel therapeutics for the prevention of brain pathology following status epilepticus. |
| Databáze: | OpenAIRE |
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