Abstracts

Rationale: Febrile seizures (FS) account for ~20% of all pediatric neurological disorders and are the most common convulsive seizure disorder to affect infants and children. FS has been linked to hyperthermia-induced respiratory alkalosis but, the mechanism of action is unknown. As transient receptor potential vanilloid-1 (TRPV1) receptors are activated by heat, sensitized by inflammatory mediators and are present in peripheral respiratory centers (vagus nerve), we hypothesize that these receptors may be critical to the pathogenesis of FS. Methods: Experimental FS (EFS) was induced in postnatal day (P) 10 rats by the heated dry air method, and seizure threshold temperature and latency were assessed following intraperitoneal (i.p.) or intracerebroventricular (i.c.v.) injection of the TRPV1 agonist, piperine (PIP), and/or antagonist, AMG-9810. We also assessed EFS expression in P10 TRPV1-KO mice treated i.p. with PIP, to confirm that the effects of PIP were TRPV1-mediated. Ventilation and the rate of expired CO2 (a measure of respiratory alkalosis) were assessed using head-out plethysmography following treatment with the TRPV1 ligands. PIP-treated rats were also exposed to 5% CO2 to determine its effect on EFS expression. To implicate TRPV1 receptor localized in the vagus nerves in the pathogenesis of FS we assessed the effects of PIP on EFS in rats in which the vagus nerves were sectioned bilaterally or in rats in which an inhibitory DREADD (Designer Receptors Exclusively Activated by Designer Drugs) was expressed in TRPV1-containing cells of the nodose ganglia. Results: PIP administered i.p. reduced the seizure threshold temperature and latency ~2-fold (p < 0.002), and this effect of PIP was associated with an exaggerated respiratory response to hyperthermia (p < 0.001) and significantly increased rate of expired CO2 (p < 0.02). Pre-treatment with AMG-9810, significantly reversed these effects of PIP (p < 0.02). I.c.v. administration of the TRPV1 ligands had no effect on either EFS expression or the respiratory response to hyperthermia. The effect of PIP to reduce the EFS thresholds was completely abolished in TRPV1-KO mice (p < 0.001). There was also a mild anti-convulsant effect of TRPV1 deletion on seizure latency (p=0.041). Exposure to 5% CO2 completely blocked EFS in 4/9 PIP-treated rats, and significantly attenuated EFS in the remaining 5 PIP-treated rats (p < 0.001). Bilateral vagotomy reversed the effects of PIP on EFS (p < 0.01) and the respiratory response to hyperthermia (p < 0.01). DREADD-mediated inhibition of TRPV1-expressing cells in the nodose ganglia of the vagus nerves significantly attenuated the effects of PIP on EFS threshold temperature (p=0.031) and latency (p=0.001). Conclusions: These results indicate that sensitization of the TRPV1 receptor prior to heat exposure, exacerbates the expression of EFS, via a peripherally-mediated respiratory mechanism involving the vagus nerve. Funding: ACHRI, ACHRI-CIHR Training Program in Genetics, Child Development and Health, AIHS