Abstracts

Rationale:

Rationale:
Stress has a profound impact on the pathophysiology of neurological disease. In epilepsy, 30-40% of patients identify stress as their most common seizure trigger (Fisher et al., 2000, Nakken et al., 2005, Haut et al., 2007). Preclinical studies have suggested that stress and/or excess glucocorticoid exposure can decrease the seizure threshold, effectively worsening the epilepsy phenotype (Koe et al., 2009 and Castro et al., 2012). Correspondingly, glucocorticoid receptor (GR) antagonists are being tested for their therapeutic potential against epilepsy. The pharmaceutical drug C108297 ([(R)-4a-ethoxy-1-(4-fluorophenyl)-6- (4-trifluoromethylbenzenesulfonyl)-4,4a,5,6,7,8-hexahydro-1H- 1,2,6-triazacylopenta[b]naphthalene]) (Corcept Therapeutics, Menlo Park, CA) is a non-steroidal compound with a high and selective affinity toward GRs (Ki 0.9nM). This drug offers a 1000-fold lower affinity for the progesterone, estrogen, androgen and mineralocorticoid receptors (Clark et al., 2008). Importantly, with both agonistic and antagonistic properties, C108297 preserves negative feedback control of glucocorticoid levels (Zalachoras et al., 2013 and Asagami et al., 2011). Here, we tested the hypothesis that excess glucocorticoid receptor activation contributes to the development of temporal lobe epilepsy in an animal model by blocking GR signaling with C108297.
Method:
Methods:  Mice were treated with either C108297 (30 mg/kg) or vehicle for 18 days following pilocarpine-induced status epilepticus. Baseline and stress-induced glucocorticoid secretion were quantified to determine whether drug treatment could mitigate HPA axis hyper-reactivity. To quantify seizure severity, brains were analyzed via immunohistochemistry for Fos protein activation, granule cell displacement, mossy cell loss, microgliosis and astrocytosis. To determine whether the treatment had antiepileptogenic properties, a separate cohort of mice underwent continuous video-EEG monitoring for 20 days following the cessation of drug treatment. Seizure frequency and duration were quantified in NeuroScore.
Results:
Results: Three-week treatment with the GR modulator C108297 reduced the overall incidence of seizures (two-way RM ANOVA F(1,20) =2.594 p =0.0005) and attenuated excess baseline and stress-induced corticosterone release (two-way RM ANOVA, [F(1,26) = 23.9 p< 0.001]; post hoc p < 0.0001). Treatment also decreased atypical stress-induced activation of the paraventricular nucleus (two-way ANOVA: [F(1,19) =4.487 p =0.048]; post hoc p =0.020), hippocampal reactive gliosis (two-way ANOVA: { F(1,23) =60.264 p < 0.001]; post-hoc p < 0.001) and aberrant migration of hippocampal granule cells (two-way ANOVA [F(1,23) =7.649 p =0.011]; post-hoc p =0.005).
Conclusion:
Conclusions: Our results provide preclinical data suggesting excess glucocorticoid signaling contributes to the development of epilepsy and associated comorbidities. These findings support the development of glucocorticoid receptor modulators as adjunctive pharmacological therapy for epilepsy.
Funding:
:This work was supported by the National Institute of Neurological Disorders and Stroke-National Institutes of Health (Grants R01NS065020 and R01NS062806 to Danzer and F30NS095578 to Wulsin) and the National Institute of General Medical Sciences (Grant T32-GM-063483 to Wulsin). The drug used in this study (C108297) was obtained from Corcept Therapeutics, Inc.