Abstracts

Rationale: The infantile spasms syndrome is an epileptic encephalopathy manifesting with epileptic spasms and usually leads to poor epilepsy and cognitive outcomes. The current therapies are not always effective or are associated with serious side effects. In the recently developed multiple-hit rat model of infantile spasms syndrome (Scantlebury, Galanopoulou et al., 2010), epileptic spasms do not respond to adrenocorticotropin hormone (ACTH) and are only transiently responsive to vigabatrin, rendering this a model of refractory epileptic encephalopathy. We tested on this multiple-hit pharmacoresistant model the efficacy of the galanin receptor 1 preferring analog, NAX5055, which was shown to have anticonvulsant effects in other seizure models (White HS. et al, 2009). Methods: Postnatal day 3 (PN3) male Sprague-Dawley rats underwent right intracerebral infusions of doxorubicin and lipopolysaccharide. NAX5055 (0.5, 1, 2, or 4 mg/kg) or vehicle were injected intraperitoneally (i.p.) in epileptic pups at PN4 after the onset of spasms. Epileptic spasms were video-monitored for 1 hour before and 5 hours after injection (n=11-14 per group). We assessed neurodevelopmental reflexes 2 hours after injection and measured vital signs (respiratory function, heart rate, pulse distension and oximetry) and blood glucose 4 hours after injection. We conducted the study as a randomized blinded study.Results: No acute effect of NAX5055 on spasm frequency after the single dose of NAX5055 was observed. The highest dose of NAX5055 (4mg/kg i.p.) had a significant effect on glucose levels 4 hours post injection(Mean blood glucose level 4 hours post NAX 4mg/kg injection = 116.2 mg/dl, post VEH injection = 82 mg/dl). Neurodevelopmental reflexes or vital signs were not affected and there was no significant increase in mortality.Conclusions: This study shows that NAX5055 has no significant acute efficacy on spasms in the multiple hit modelof medically refractory infantile spasms. These results are further proof that the pharmacosensitivity of infantile spasms is different from other seizure types animal models.We however cannot exclude the possibility that in the multiple-hit model repetitive dosing with a galanin analog may have delayed efficacy in suppressing spasms. Developing pups tolerated well the doses of NAX 5055. Significantly increased blood glucose levels were observed only in animals with the highest tested dose.