Abstracts

Rationale: Infantile spasms, whose main cause is malformations of cortical development (MCDs), is a destructive epileptic encephalopathy that occurs in infancy. However, the pathogenesis remain unclear, and symptomatic treatment is mostly used. We explored a treatment based on molecular changes using the infant rats with MAM-induced MCD.

Methods: At gestational day 15, two dosages of MAM (15mg/kg, i.p.) were injected to pregnant rats to produce MCD and normal saline to controls. The offspring were sacrificed in postnatal day 15 (P15) and their cortex were separated for proteomic analysis. Another set of prenatally MAM-exposed rats were pretreated with recombinant human IGF1 (rhIGF1, 0.5mg/kg/dose, P12 to P14 twice a day) and the number and latency to onset of spasms were monitored for 90 minutes after the NMDA (15mg/kg i.p.) injection at P15 or obtained cortical tissue to perform western blot.

Results: Using ingenuity pathway analysis based on proteome, significant activation of IGF-1 signaling pathway was found in rats with MAM-induced MCD compared to normal controls (-Log (P value) = 8.1, z-score = 1.789).

Prenatally MAM-exposed rats with 3days of rhIGF1 treatment (n = 17) showed delayed onset to tailing (p = 0.021), first spasms (p = 0.006) and full spasms (p = 0.002) and decreased number of spasms (p < 0.001) compared to vehicle treated controls (n = 18). IGF-1 pretreatment also resulted elevation AKT (p = 0.018) and decreased phospho-GSK3beta (p = 0.009) protein expressions at P15 rat cortex (n = 11, vehicle n = 9).