Abstracts

Rationale: Patients with early-onset Alzheimer’s disease (EOAD) experience focal seizures at a greater rate than similarly aged individuals without AD, which could accelerate functional decline. Use of antiseizure drugs (ASDs) have thus been proposed as a possible disease-modifying strategy. Genetic variants in presenilin 2 (PSEN2) are associated with EOAD and these patients also experience seizures. PSEN2 variants lead to loss of normal function of the catalytic component of the g-secretase enzyme that promotes pathologic amyloid beta (Ab) processing. While studies have evaluated the impact of Ab overexpression on anticonvulsant efficacy of ASDs, seizure susceptibility and ASD efficacy in PSEN2 variant models is significantly underreported. We thus hypothesized that specific mechanistic classes of ASDs may differentially control focal seizures in diverse AD models. This study established the dose-related anticonvulsant efficacy of mechanistically distinct ASDs in the 6 Hz focal seizure test evoked in adult PSEN2 knockout (KO) mice to better guide the personalized therapeutic management of focal seizures in EOAD._x000D_
Methods: The median effective dose (ED50) of prototype ASDs (valproic acid (VPA), carbamazepine (CBZ), and perampanel (PER) by the i.p. route) was established with at least a 4-point dose-response (n=8 mice/dose) in the 6 Hz test in male and female PSEN2 KO and WT C57Bl/6J mice aged 3-4 months-old. Minimal motor impairment (MMI) was assessed prior to seizure testing on the fixed-speed rotarod to define a therapeutic index of each ASD. Lastly, c-Fos immunohistochemistry was used to define acute neuronal activation of PSEN2 KO and WT mice 90 min after an evoked 6 Hz seizure.

Results: The ED50 of VPA in male PSEN2 KO mice was 62.7 mg/kg [48.6-90.8]; significantly lower than the ED50 for age-matched male WT mice (158 mg/kg [108-242]). In females, the VPA ED50 in PSEN2 KO mice was 93.3 mg/kg [39-159], while in age-matched WT mice it was 163 mg/kg [120-235]. The ED50’s of CBZ and PER in both male and female PSEN2 KO mice did not substantially differ from WT. However, there were marked genotype-related shifts in the therapeutic index for both agents: 0/10 of the PSEN2 KO male mice exhibited MMI following high-dose CBZ (40 mg/kg) administration whereas 6/6 of male WT mice were impaired at this dose. Female PSEN2 KO and WT mice exhibited a similar trend in MMI at this CBZ dose (1/8 PSEN2 KO vs. 3/5 WT mice). At the highest PER dose tested (2 mg/kg), PSEN2 KO mice exhibited less rotarod impairment (3/8 males, 0/8 females), whereas WT mice of both sexes were impaired (5/8 males, 3/8 females)._x000D_
Conclusions: Acute ASD efficacy and tolerability in the 6 Hz focal seizure test may be significantly altered with loss of normal PSEN2 function. Notably, PSEN2 KO male mice were more sensitive to acute VPA administration than WT in this test. However, this sensitivity was not conserved across all ASDs tested. The acute therapeutic indices of both CBZ and PER were widened. This study suggests that seizures in discrete EOAD populations may benefit from rational selection of clinically-approved ASDs based on primary pharmacological mechanism.

Funding: NIA R01AG067788