(551) Validation of in-house drug-in-food pellets for antiseizure drug screening in three epilepsy models at the NINDS-Funded Epilepsy Therapy Screening Program Contract Site

Rationale: Compared to injections or gavage, oral drug administration in food allows for a less stressful administration route to rodents. While there are commercially available drug pellets, use of these pellets is limited to non-scheduled drugs. Therefore, we have developed an in-house drug-in-food pellet formulation and evaluated efficacy and palatability in three epilepsy models.

Methods: Drug and no-drug control pellets were generated using wet granulation and pressed by using a tablet press. Pellets were delivered either manually or through automated feeders. All animals were monitored using continuous video EEG (vEEG).
Dravet syndrome mouse model: Scn1a^A1783V/WT mice were implanted with a cortical surface electrode for vEEG. After a five-day baseline, mice were given in-house drug pellets with carbamazepine (10g CBZ/kg chow) or no-drug pellets for seven days, followed by a five-day washout. Following the washout, control and CBZ groups were switched.
Intra-amygdala kainic acid (IAK) mouse model: Mice were implanted with a cannula into the amygdala for KA administration and a bipolar electrode in the CA1 region of hippocampus. Following KA administration (three to four weeks), mice experiencing spontaneous seizures were divided into two groups. All mice were fed control pellets for seven days and then fed either drug (3g CBZ/kg chow) or control pellets. After treatment (seven days) and a washout period (seven days), mice were crossed over to the opposite treatment group for additional seven days.
Kainic acid-induced status epilepticus (KASE) rat model of chronic recurrent seizures: Rats were selected for study ten-12 weeks following KA administration. After acclimation to control pellets, all rats were placed on drug pellets (10g CBZ/kg chow) for 14 days.

Results: Scn1a^A1783V/WT mice: Over the seven days, CBZ (N=9) significantly increased (P=0.04, Mann-Whitney) the average daily seizure frequency and the time spent seizing as compared to no-drug control pellets (N=10). Additionally, the cumulative seizure incidence was significantly higher on days 6 (P=0.01) and 7 (P=0.002, 2way ANOVA) as compared to control.
IAK model: Over the seven days, CBZ did not significantly affect average seizure frequencies (N=15; P=0.7963, Mann-Whitney).
KASE model: Over 14 days, CBZ significantly decreased the average daily seizure frequency as compared to no-drug control (N=15; p=0.0175). Treatment with commercially available pellets led to similar results in seizure burden and seizure freedom (N=10, p< 0.001).

Conclusions: This data demonstrates that in-house formulated pellets with CBZ are palatable. Our pellets performed comparably to commercial pellets in the KASE rat model. Use of this sodium channel blocker increased seizure frequency in the Scn1a^A1783V/WT mice, demonstrating bioavailability in mice. The pellets were without effect in the IAK mouse model, although mice did eat the pellets. This lack of efficacy may be dose related and correlates with i.p. data. Future work will compare the effect of the in-house pellets to commercially available pellets in the two mouse models.

Funding: Please list any funding that was received in support of this abstract.: NINDS HHSN271201600048C