Metyrapone abolishes Spike-Wave Discharge seizures in GAERS by reducing stress hormones.

Abstract

Stress is one of the most commonly reported triggers for seizures in patients with epilepsy, although the mechanisms which mediate this effect are not established. The clinical evidence supporting this is derived from patient's subjective experience of stress, and how this influences their own seizures. Animal models can be used to explore this phenomenon in controlled environments, free from subjective bias. Here we used GAERS, a genetic rat model of absence epilepsy, to explore the influence of stress and stress hormones on spontaneous seizures. Adult male GAERS (n=38) and Non-Epileptic Controls (NEC: n=4) were used. First, rats were subjected to 30 minutes restraint stress to assess Hypothalamic-Pituitary-Adrenal (HPA) axis function. Next, we assessed the effects of 30-minute noise stress, and cage tilt stress, on Spike-Wave Discharge seizures in GAERS. We then performed pharmacological experiments to assess the direct effects of stress hormones on seizures, including corticosterone, metyrapone and deoxycorticosterone. GAERS exhibited elevated baseline corticosterone levels, compared to NEC rats. Noise stress and cage tilt stress significantly enhanced seizure incidence (p<0.05), but only during stress periods. Exogenous corticosterone administration also significantly increased seizure occurrence (p<0.05). Metyrapone, an inhibitor of corticosterone synthesis, completely abolished seizures in GAERS, and seizures remained suppressed for over 2 hours. However, deoxycorticosterone, the precursor of corticosterone, increased seizures. These results suggest that GAERS exhibit elevations in stress hormones, and this may contribute to seizures. Inhibiting corticosterone synthesis with metyrapone prevents seizures in GAERS, and shows potential for repurposing this drug as a future anti-seizure medication.