Abstracts

RATIONALE: NMDAR antagonists inhibit epileptogenesis in animal models. But high-affinity competitive NMDAR antagonists exacerbate seizures in some epilepsy patients. Similarly, we showed previously that chronic treatment of hippocampal slice cultures with the high-affinity competitive NMDAR antagonist, D-APV, enhanced electrographic granule cell seizures (Bausch & McNamara 2001). Seizure enhancement was associated with mossy fiber sprouting (MFS), a synaptic rearrangement postulated to contribute to epileptogenesis.
METHODS: To examine whether other classes of NMDAR antagonists inhibit epileptogenesis and whether the effects of these antagonists on epileptogenesis are linked to mossy fiber sprouting, hippocampal slice cultures were treated chronically with vehicle; APV (high affinity competitive); Ro 25-6981 or ifenprodil (NR2B-selective); memantine (moderate-affinity uncompetitive) or DCKU (glycine site). At 17-21 DIV, electrographic granule cell seizures were recorded extracellularly and MFS was detected by Timm stain.
RESULTS: In response to GABA[sub]A[/sub]receptor blockade with bicuculline (BMI), vehicle-treated cultures exhibited multiple recurrent seizures. In comparison with vehicle-treated cultures, total BMI-induced seizure durations were increased by 28.44%, 88.44% and 82.87% in memantine-, DCKU- and APV-treated cultures, respectively. In contrast, total BMI-induced seizure durations were reduced by 65.8% and 67.31% in Ro 25-6981- and ifenprodil-treated cultures, respectively. In parallel, moderate MFS was observed in memantine-, DCKU- and APV-treated cultures whereas only minimal MFS was noted in vehicle-, Ro 25-6981- and ifenprodil-treated cultures.
CONCLUSIONS: These results indicate that NR2B-selective antagonists inhibit epileptogenesis and support the hypothesis that MFS contributes to epileptogenesis.
[Supported by: USUHS C075HK and the Defense Brain & Spinal Cord Injury Program]