The glucocorticoid receptor specific modulator CORT108297 reduces brain pathology following status epilepticus.
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.
['Wulsin|Aynara C|AC|', 'Kraus|Kimberly L|KL|', 'Gaitonde|Kevin D|KD|', 'Suru|Venkat|V|', 'Arafa|Salwa R|SR|', 'Packard|Benjamin A|BA|', 'Herman|James P|JP|', 'Danzer|Steve C|SC|']
D000818:Animals D001372:Aza Compounds D004305:Dose-Response Relationship, Drug D006576:Heterocyclic Compounds, 4 or More Rings D006624:Hippocampus D008297:Male D051379:Mice D010862:Pilocarpine D011965:Receptors, Glucocorticoid D013226:Status Epilepticus
Glucocorticoid receptor Status epilepticus Hypothalamic-pituitary-adrenal axis Corticosterone (CORT) Epilepsy Pharmacological therapy Seizures