Abstracts

Rationale: Febrile seizures (FS), which are the most common convulsive seizure disorder to affect infants and children, account for ~20% of all pediatric neurological disorders. Whether simple or atypical, FS are not benign. Simple FS increase the risk of cognitive deficits if they occur in babies <1 year old and increase the risk of sudden unexpected death in childhood, while atypical FS cause an 8-fold increase in the risk of developing epilepsy. Effective treatment options are still unavailable for FS, due particularly to the still poorly understood pathogenesis. Since inflammation has long been considered to play a major role in the pathogenesis of FS, we investigated the mechanism of action of inflammation on FS susceptibility in the heated dry air model. Methods: An inflammation-based model of FS was developed by administering 400 µg/kg LPS i.p. to neonatal rats from postnatal day (P) 6-10 or P11-15. At P10 or P15, LPS was administered 3 hours prior to blood collection, induction of FS or plethysmography. The rat cytokine array 27 Plex (RD27) assay was used to assess serum cytokines. FS was induced by the heated dry air method in the presence or absence of the TRPV1 antagonist, AMG-9810, and the seizure threshold temperature (T_body) and latency assessed. Head-out plethysmography was used to assess the thermal hyperpneic response in the model. Results: Prior to FS, LPS induced a 100-700% increase in the serum levels of several chemokines and pro-inflammatory cytokines known to sensitize or transactivate TRPV1 receptors including IL-1ß (p=0.019), MIP-1a, MCP-1, IP-10 and TNF-a (all pbody (p=0.006), the ?T_body from the start of hyperthermia to seizure onset (p=0.001) and the seizure latency (pbody: p=0.027; ?T_body: p<0.001; seizure latency: p=0.005). At P15, only the seizure latency was significantly reduced by LPS treatment (p=0.041). LPS exacerbated the thermal hyperpneic response in P10 rats as indicated by a significantly higher tidal volume (p=0.006), no difference in the breathing frequency and a corresponding higher rate of expired CO2 (p=0.05) during hyperthermia compared to vehicle-treated controls. At P15, however, the LPS-mediated breathing response to hyperthermia more closely resembled thermal tachypnea as indicated by a significantly increased breathing frequency (p=0.037) with no corresponding change in tidal volume or rate of expired CO2. Conclusions: These results indicate that bacterial exposure in young rats induces an inflammatory cytokine/chemokine profile that favors TRPV1 sensitization and alters the breathing response to hyperthermia in an age-dependent fashion, which in turn increases susceptibility to febrile seizures. Funding: Canadian Institute of Health ResearchAlberta Children's Hospital Research Institute