Abstracts

Rationale: Alzheimer’s disease (AD) is considered a risk factor for acquired epilepsy. Patient with AD has increased incidence of unprovoked seizures, which may lead to faster progression of AD symptoms and greater cognitive impairments. Previous studies showed that aged Tg2576 mice, a well-studied AD model that overexpresses human amyloid precursor protein (APP), are vulnerable to acquired epileptogenesis. This study aimed to assess the effects of three antiepileptic drugs on the epileptogenic process induced by amygdala kindling in these animals. Methods: Aged Tg2576 mice (13-25 months; n=5-7/group) were treated with either lacosamide (LAC, 5 mg/kg/day), brivaracetam (BRV, 10 mg/kg/day), levetiracetam (LEV, 150 mg/kg/day) or vehicle (VEH, 0.9% sodium chloride). Treatment was delivered via subcutaneously implanted osmotic pumps for 30 days prior to and during the stimulation period.  A constant current stimulation at the respective afterdischarge threshold value (ADT) for each animal, was given every day once a day until they had either 3 consecutive class 5 seizures or was deceased, whichever occurred sooner. The animals that survived were euthanized, transcardially perfused and brains were excised. Number of stimulations to first class five seizure, ADT value, seizure duration and death during kindling were compared between the treatment groups. APP and Aß peptide expression was measured in amygdala, hippocampus and cortex by western blot. Results: There was no difference in afterdischarge threshold between the treatment groups. A slower progression of the seizure severity was observed after treatment with BRV and LEV compared to VEH (p < 0.0001 and p < 0.05). The animals treated with BRV required significantly more stimulations to reach the first class V seizure. 50% of the mice in the VEH group died immediately after kindled seizures compared to none in the BRV group. There was no difference in APP or Aß expression in the selected brain regions between the groups. Conclusions: These results show that treatment with BRV, and to a lesser extent, LEV, treatment may be antiepileptogenic in AD mice without affecting APP or Aß expression. Further investigations on the mechanisms of action behind this effect are necessary to better understand the potential of BRV and LEV as disease-modifying drugs in the AD context. Funding: Department of Medicine, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, The Royal Melbourne Hospital;UCB Pharma;