Authors :
Presenting Author: Amy Chappell, MD, FAAN – Avenue Therapeutics
Alexis Evrard, PhD – Synapcell; Hugo Monchal, MSc – Synapcell; Corinne Roucard, PhD – Synapcell; Alexandra MacLean, MD – Avenue Therapeutics
Rationale: GABAA receptor potentiators are in various stages of development for the treatment of patients with epilepsy. BAER-101 (formerly AZD7325) is a selective potentiator of
α2/3-containing GABAA Receptors (GABAARs) with a lower liability for sedation, dizziness, and ataxia than that of non-selective potentiators. Prior published data have confirmed antiseizure effects of BAER-101 in genetic models of Dravet and Fragile X Syndromes. The aim of the present study was to determine efficacy in a model of generalized seizures. The Genetic Absence Epilepsy in Rats from Strasbourg (GAERS) model is widely accepted for evaluating novel antiseizure medications and is translatable. Methods: Fourteen adult male GAERS were maintained and used in a facility approved and monitored by the animal care and use controls in France in accordance with all ethical guidelines. Recording electrodes were implanted under general anesthesia using stereotaxic methods. Four active monopolar electrodes were positioned bilaterally over the frontal and parietal cortices. The approximate coordinates for the frontal cortex were: AP +2 mm, ML +/- 3 mm (from bregma as reference). The approximate coordinates for the parietal cortex were: AP -7 mm, ML +/- 3 mm. A fifth electrode was placed on the cerebellum as reference. EEG signals were analyzed to count spike-wave discharges (SWDs). BAER-101 was given orally in doses of 3-100 mg/kg and subsequently, in doses of 0.1-3.0 mg/kg. Diazepam was used as a positive control (2 mg/kg, IP). A cross-over protocol was used for each rat with a minimal wash-out period of seven days. EEG recordings were collected on freely moving and awake animals for 40 min pre-administration (baseline period) and 90 min post-administration using SystemPlus Evolution (Micromed). EEG recordings were subsequently analyzed offline and quantified blindly by an expert on our proprietary platform (CUE®), to identify SWD (Fig. 1).
Figure 1
: Example of an EEG recording in a GAERS in baseline condition. The SWD occurs spontaneously, with clear-cut start and stop well defined over the basal EEG activity.
Results: The number of SWDs was dose-dependently reduced in rats given BAER-101 (Fig. 2). When the data were summarized over the entire observation period, 0.3 mg/kg was found to be the minimal effective dose. The duration and total time in SWD were also significantly reduced by BAER-101.
Figure 2: Number of SWD per 20 min, in the vehicle condition (dark blue), diazepam at 2 mg/kg IP (light blue), and BAER-101 at 0.1 to 100 mg/kg PO (other colours). The grey arrow indicates the administration. #, ##, ###, ####: p < 0.05, 0.01, 0.001 and 0.0001 as compared to vehicle (n = 4 to 12).