Abstracts

Rationale: Febrile seizures (FS) are generalized convulsions occurring with fever caused by a bacterial or viral pathogen that is not associated with a direct CNS infection. They account for ~20% of all pediatric neurological disorders and are the most common convulsive seizure disorder to affect infants and children. FS are not benign. They increase the risk of developing epilepsy 8-fold if atypical and there is a high risk of patients with simple FS that may be susceptible to sudden unexpected death in childhood and to an increased risk of cognitive deficits if they occur in babies less than a year old. Since effective prophylactic treatments for FS are still unavailable, we investigated the effects of nine pharmacological agents on the seizure thresholds in a model of FS with or without inflammatory pre-conditioning. Methods: Inflammatory pre-conditioning was achieved by administering LPS (400 µg/kg) i.p. to neonatal rats from postnatal day (P) 6-10. At P10, LPS was administered 3 hours prior to induction of FS. The pharmacological agents were injected i.p. 30 minutes prior to FS in rats that were or were not exposed to inflammatory pre-conditioning. FS was induced by the heated dry air method, and the seizure threshold temperature (Tbody) and latency assessed. Results: LPS significantly increased serum levels of the pro-inflammatory agents IL-1β, TNF-α and bradykinin, and reduced the absolute seizure threshold Tbody (p=0.006), the ?Tbody from the start of hyperthermia to seizure onset (p=0.001) and the seizure latency (p=0.0007). In the absence of LPS pre-treatment, none of the pharmacological agents had an effect on the seizure thresholds, except diclofenac (an NSAID), which increased the seizure threshold Tbody (p=0.038). However, following LPS pre-conditioning, AMG-9810 (TRPV1 antagonist; p=0.027), valproate (anti-convulsant drug; p=0.015), diclofenac (p=0.023) and β-hydroxybutyrate (ketone; p=0.028) significantly increased the absolute seizure threshold Tbody, while AMG-9810 (p=0.0002), carbamazepine (anti-convulsant drug; p=0.003) and acetaminophen (anti-pyretic; p=0.004) significantly increased the seizure threshold ?Tbody, and AMG-9810 (p=0.005), carbamazepine (p=0.049), valproate (p=0.002) and diclofenac (p=0.0003) significantly prolonged the seizure latency. Conclusions: These results indicate that certain pharmacological agents have a different profile of effectiveness in treating FS, depending on whether inflammation is involved. The TRPV1 antagonists, AMG-9810, had the strongest effect, supporting a significant role for TRPV1 in FS genesis, while valproate, carbamazepine and diclofenac had moderate effects and β-hydroxybutyrate and acetaminophen had only mild effects. Funding: Alberta Children’s Hospital Research Institute (ACHRI), University of Calgary Research Enhancement Program, Canadian Institutes of Health Research (CIHR), ACHRI-CIHR Training Program in Genetics, Child Development and Health and Alberta Innovates: Health Solutions (AIHS).