Abstracts

Rationale: Infantile spasms (IS) is an infantile epileptic encephalopathy associated with cognitive and behavioral deficits and increased mortality. Vigabatrin, a GABA transaminase inhibitor, is one of the few treatments available for IS. Here, we test the efficacy in suppressing spasms and tolerability profile of a new vigabatrin analog, CPP-115, in the multiple-hit rat model of ACTH-refractory symptomatic IS (DLP model). In previous studies, vigabatrin only transiently suppressed spasms in the DLP model (postnatal day 5 (PN5) only), but was associated with increased sedation and consequently mortality due to poor feeding.Methods: We used the multiple-hit rat model of IS (DLP), in which PN3 male rats receive right intracerebral injections of doxorubicin and lipopolysaccharide (PN3) followed by intraperitoneal (i.p.) injection of p-chlorophenylalanine (PN5). On the first day of spasms (PN4), the rats were recorded by video camera for three hours (two in the morning, one in the afternoon) for baseline spasm counts, then monitored for another two hours after treatment. On subsequent days, rats were monitored for two 2h sessions, one in the morning and one in the afternoon. Rats received vehicle or CPP-115 (provided by Dr Steven Miller, Catalyst Pharmaceutical Partners, Inc), starting at PN4, after the onset of spasms. The following doses of CPP-115 were compared: 0.1, 1, 5, or 25 mg/kg/day i.p. between PN4-12 (n=9-11 rats/group). A separate group of rats received vehicle or CPP-115 (1 mg/kg/day i.p.; PN4-12; n=6-7 rats/group), but on PN6-7 they were implanted with epidural EEGs (Pinnacle Technology) and video-EEG monitoring commenced 24 hours later. Scoring of behavioral and electroclinical spasms was done by an investigator blinded to treatment. Daily weights and neurodevelopmental reflexes (open field activity, surface righting time, negative geotaxis) were done between PN3-20. Brains were collected for histology at PN20.Results: High doses (CPP-115 at 5 and 25 mg/kg/day i.p.) were lethal (100% mortality by PN8, with 9/9 and 2/2 rats dying respectively). The lower CPP-115 doses (0.1-1 mg/kg/rat) were well tolerated and were not associated with significant mortality; 2/9, 2/10 and 0/9 pups died by PN20 in the vehicle, 1 and 0.1 mg/kg/day CPP-115-treated groups respectively. CPP-115 at doses 0.1 or 1 mg/kg/day suppressed spasms between PN5-7 in a dose-dependent fashion. CPP-115 did not affect the neurodevelopmental reflexes.Conclusions: CPP-115 is a candidate new treatment for IS, with better efficacy/tolerability profile than vigabatrin in the DLP model of ACTH-refractory IS. Funded by NIH NINDS/NICHD grant NS62947, NINDS NS20253 and the Heffer Family Foundation.