Abstracts

Rationale: Clinically, as well as in animal models, hypoxic seizures (HS) in the immature brain are associated with long-term cognitive and emotional behavioral deficits. We have recently shown that a transient post-HS administration of CEP-701 (lestaurtinib), attenuates the HS-induced short-term brain excitability. Here we tested the effect of such treatment on long-term learning and emotional behaviors in periadolescent rats following early postnatal day 10 (P10) HS.Methods: P10 Long–Evans male rat pups were divided into 4 groups. The HCEP group (n=14) received 2 doses of CEP-701 intraperitoneally, 3 mg/kg/dose immediately after and 12 hours after HS. The HV group (n=14) received vehicle after HS. HS was induced by 15 min of graded exposure to 7-4% O2. Controls were manipulated under normoxic conditions and received CEP-701 (NCEP, n=12) or vehicle (NV, n=12). Behavioral panels including forced swim test (FST), open field, light-dark box, and active avoidance were performed in the periadolescent age (P21-P45). The shuttle box used in the active avoidance test was modified by adding visual cues to the right chamber, in which the shock was not signaled by a tone, and delivered more frequently than in the left chamber. Scalp electroencephalography (EEG) was performed over 24 hours at P45.Results: Immobility significantly increased in the last 2 minutes of day 1 of FST (p < 0.01), and in the last 3 minutes of day 2 of FST in the HCEP and NV groups (p < 0.03) but not in the HV group (p > 0.05). Moreover, in the last 3 minutes of day 2 of FST, the average immobility in the HCEP group (18.17%) was similar to the NV group (12.97%), but significantly higher than the HV group (6.07%, p < 0.02). There was no difference in average immobility in all other comparisons. Context avoidance testing after training sessions revealed that the CEP-treated rats made significantly less erroneous right chamber entries than the HV group (p < 0.05) and were comparable to the normal controls (p > 0.05). There were no differences in learning avoidance of tone or context during training sessions between all groups (p > 0.05). The total distance traveled, and the time spent in exploring objects placed in the center of the open field were comparable in all groups (p > 0.05). In the light dark box test, the time spent on the lit side of the chamber, and the number of transitions between the chambers was comparable in all groups (p > 0.05). None of the 4 groups experienced seizures over the 24 hours of recording.Conclusions: Transient post-HS treatment with CEP-701 normalized both long-term behavioral deficits in the FST and contextual learning in the modified active avoidance test. Unexpectedly, HS induced an increase in struggling in the FST rather than immobility; an effect that might be related to deficits in learning futility. Given its known clinical safety profile, CEP-701 is a promising agent that could prevent the long-term behavioral sequela of early life hypoxic seizures.