Abstracts

Rationale: Some antiseizure drugs (ASDs) are associated with cognitive liability in patients with epilepsy. ASDs that do not impair cognitive function are thus important to identify. Little is known about the effect of prototype ASDs on cognitive performance in preclinical rodent models. Even less data exists on the acute effects of prototype ASDs on cognition in rodents with chronic seizures. Predicting the risk for cognitive impact with preclinical models may supply valuable differentiation data for drug development. This study thus determined the acute effect of therapeutically-relevant doses of prototype ASDs on cognitive performance in naïve rodents and corneal kindled mice.Methods: ASDs tested included: phenytoin (PHT); carbamazepine (CBZ) valproic acid (VPA); lamotrigine (LTG); phenobarbital (PB); tiagabine (TGB); ezogabine (EZG); topiramate (TPM); levetiracetam (LEV). Rodents received a single i.p. ASD dose equivalent to the maximal electroshock (MES) ED50 (mice, rats), or median dose necessary to elicit minimal motor impairment (TD50; rats). Performance was tested at the time of peak effect of the ASD. Models of learning and memory in naïve adult male rodents were Novel Object/Place Recognition (NOPR) with CF-1 mice (n=12/group), and Morris water maze (MWM) with Sprague-Dawley rats (n=10/group) using a single-day, 5-trial drug screening protocol. A cohort of mice (n=8/group) also underwent corneal kindling (CK) to assess the combined effect of chronic seizures and drug administration on cognitive performance in NOPR. Mice that did not fully kindle were included as a partially-kindled (PK) cohort to examine any effect of electrical stimulation on NOPR; results were compared to those obtained in sham kindled (SK) and age-matched (AM) mice.Results: In NOPR with naïve mice, CBZ and VPA reduced time spent with the novel object. Doses equivalent to MES ED50 did not affect performance of naïve rats in MWM. However, administration of TD50 doses of PB, EZG, TPM, and VPA reduced MWM performance. Furthermore, CBZ, LEV, PHT and VPA in CK, PK, SK and AM mice induced a kindling x treatment interaction in NOPR. Relative to vehicle-treated CK mice, no treatment affected fully CK mice, whereas CBZ improved performance in PK mice. PHT reduced time spent with the novel object in both SK and AM mice. As in naive mice, VPA impaired performance in AM mice, but normalized performance in CK mice.Conclusions: The acute effects of prototype ASDs on cognitive performance utilizing naïve rodents suggest differences in response. Furthermore, administration of select ASDs to mice with a history of chronic seizures, i.e., kindled mice, suggests no significant effects on working memory at the doses and times tested. These data highlight the value of testing acute effects of investigational ASDs on learning and memory in diverse preclinical models. Future studies following chronic administration of prototype ASDs in models of learning and memory with naïve or chronically-seized rodents may inform on the risk for cognitive liability in patients with epilepsy and complement drug development efforts to identify novel ASDs.