PHENOBARBITAL MODIFIES SEIZURE-RELATED BRAIN INJURY IN THE DEVELOPINGBRAIN

To investigate the potential role of drug therapy in preventing or exa cerbating seizure-related brain injury in the prepubescent brain, we a dministered kainic acid to rats at postnatal day 35. Therapy with dail y phenobarbital was started directly before or 1 day after kainic acid was administered, and was continued through postnatal day 153. Rats r eceiving phenobarbital had therapeutic concentrations during most of t he 24-hour dosing period, but also experienced supratherapeutic peak c oncentrations. The animals were subsequently tested using the water ma ze (a measure of visuospatial memory), open field (a measure of activi ty level), and handling tests (a measure of emotionality). The frequen cy of spontaneous recurrent seizures was monitored during and after ph enobarbital therapy. Kainic acid resulted in status epilepticus on pos tnatal day 35 in all the rats that received it but those receiving phe nobarbital first manifested a shorter and less severe status epileptic us as compared to the rats given kainic acid alone. Rats starting phen obarbital immediately before kainic acid was administered did not diff er from control rats on behavioral testing and had no subsequent spont aneous recurrent seizures and no histological lesions. Rats receiving kainic acid alone performed significantly poorer than did control rats in the water maze, were more aggressive, had histological lesions, an d manifested spontaneous recurrent seizures. As compared to the group treated only with kainic acid, rats receiving kainic acid followed by phenobarbital at postnatal days 36 to 153 manifested similar aggressiv eness and histological lesions, similar frequency of spontaneous recur rent seizures after phenobarbital taper, and even greater disturbances in memory, learning, and activity level. These results demonstrate th at kainic acid-related injury can be prevented by a medication working through inhibitory mechanisms; that structural and functional damage in the prepubescent brain can be prevented through strategically timed pharmacotherapy; and that treatment of spontaneous recurrent seizures alone with daily exposure to phenobarbital does not decrease, and may actually exacerbate, damage in the kainic acid model.