Abstracts

Potential side-effects of chronic antiepileptic treatment on glutamate receptors and circulating corticoids (CORT) during critical periods of brain development are unknown. Recently we reported that seizure-induced patterns of AMPA receptor expression are age-dependent. Here we questioned whether maturational changes in glutamate receptors are affected by novel antiepileptic drugs in the presence or absence of kainate (KA)-induced status epilepticus during a critical growth period, the 2nd-3rd postnatal (P) weeks of rat development. To determine whether AD treatments alter cell fate, glutamate-type receptors and plasma CORT levels, daily treatment of lamotrigine (LTG), carbamazepine (CBZ), phenytoin (PHT), or valproate (VPA) (5-50 mg/kg) was initiated on P14 and then continued daily for 7 days before status epilepticus was induced with KA on P21, an age when prominent CA1 damage first appears. Four days after seizure cessation, cell fate was monitored with silver impregnation and Nissl stains and expression of AMPA- and mGluR-type glutatmate receptors were assessed with immunohistochemistry and western blotting. Trunk blood was collected at time of sacrifice to simultaneously assay CORT levels by radioimmunoassay (RIA). In prepubescent rats, chronic treatment with any of the four ADs tested had little or no ability to attenuate KA-induced electrographic (EEG) seizures. Despite poor antiepileptic activity, LTG and VPA protected CA1 but not CA3 hippocampal neurons from seizure-induced injury as determined by Nissl and silver staining. None of the ADs had effect on the maturational differences in expression of AMPA proteins after KA; however LTG and VPA prevented seizure-induced alterations in protected areas of the hippocampus. In contrast, mGluR1a, an age-specific interneuronal marker, was prematurely elevated in CA3 pyramidal cells after KA seizures and chronic LTG or VPA treatments. Plasma CORT levels were greatly reduced below baseline in animals treated with the neuroprotective ADs. These findings suggest that premature elevations of mGluR1a-type glutamate receptors of the hippocampus with simultaneously suppressed adrenal hormone plasma levels may be underlying mechanisms of neuroprotection of novel ADs with poor antiepileptic activity. (Supported by New York Osteopathic College of Medicine of NYIT and NJ Neuroscience Institute.)