Abstracts

Rationale: Insulin-like growth factor-1 (IGF-1) is widely expressed in the brain throughout normal development and promotes neuronal survival, differentiation and maturation - particularly in the neocortex. IGF-1 is readily metabolized by an acid protease to produce a N-terminal tripeptide (glycine-proline-glutamate) called (1-3)IGF-1. This tripeptide is thought to retain strong neurotrophic properties and can readily cross the blood brain barrier where it promotes neuronal development. The concentration of IGF-1 has been reported to be abnormally low in the CSF of children with symptomatic infantile spasms. Thus we have undertaken experiments to determine if (1-3)IGF-1 could suppress spasms and hypsarrhythmia in the TTX animal model of infantile spasms. Methods: This seizure disorder was induced by a unilateral chronic infusion of TTX (12 uM) into rat somatosensory cortex beginning on postnatal day (P)11 or 12. Behavioral spasms and hypsarrhythmia are first observed between P16 and 20 and persist for several months. We used long-term (24/7) video/multielectrode array EEG recordings with high sampling rates (2048 Hz) to analyze daily spasm frequency and hypsarrhythmia. EEG electrodes were implanted after weaning on P27-30. After 5 days of baseline recordings, (1-3)IGF-1 was injected (10 mg/kg/day, i.p.) for 3 weeks. Results: Of 8 rats treated with (1-3)IGF-1, 5 became seizure free during the 3 week treatment and spasms did not recur during continuous recordings for an additional 5 weeks. TTX-infused control rats (n=9) persisted in displaying high spasm counts throughout comparable recordings periods. In 2 of the 3 remaining (1-3)IGF-1 treated rats, spasms counts decreased dramatically during treatment but resumed either during treatment or after treatment cessation. When compared to control rats, the overall effect of (1-3)IGF-1 treatment on spasm frequency was found to be statistically significant ( P < 0.02, Kruskal-Wallis ANOVA). Of the 8 (1-3)IGF-1 treated rats, 6 displayed hypsarrhythmia during baseline recordings. Hypsarrhythmia was eliminated in 4 of these 6 rats by the final day of treatment. Hypsarrhythmia persisted in 2 rats but they were animals whose spasms only transiently decreased during treatment. Seven of the 9 control rats had hypsarrhythmia during baseline recordings and all 7 had hypsarrhythmia throughout the recording periods. This difference in the presence of hypsarrhythmia between control and (1-3)IGF-1 treated rats was statistically significant (P < 0.05, Fisher Exact Test). Conclusions: Results suggest that (1-3)IGF-1 or its analogues may be an effective therapy for infantile spasms. Such compounds are currently in clinical trials for other neurodevelopmental disorders.