Influence of gabapentin on morphological changes induced by epileptiform activity in hippocampus in vitro

Introduction Gabapentin is a potent anticonvulsant though with not fully clarified mode of action. Effects on amino acid transport and direct affinity to neurotransmitter receptors (e.g. gamma-amino-butyric acid, GABA) and their postsynaptic effector systems are suspected. In our study, we exposed bicuculline, a GABA(A) receptor antagonist, to hippocampal slice cultures. Such organotypic cultures are used in particular in epilepsy research for testing anticonvulsants, as they offer a versatile test model due to their proximity to the in vivo situation. Material and methods On postnatal days 6-8, from hippocampi of Sprague-Dawley rats coronal sections were prepared and cultivated on Millicell-CM-membranes for 9 days. Between day 6 and day 9, bicuculline, gabapentin or either substance were administered to the cultures at a concentration of 100 micromolar before harvesting the slices. Degenerative or compensatory changes of receptor densities of glutamatergic and GABAergic receptors were immunohistochemically quantified by specific antibodies against the glutamate receptors GluR2 and NMDAR2, the GABA(A) receptor, and against neurofilament proteins. Results Treatment with gabapentin alone resulted in a significant reduction of the NMDAR2 density in the Cornu ammonis 1 (CA1) region of the hippocampus of about 36 % compared to controls. Bicuculline-induced significant increases of the densities of neurofilament proteins and GluR2 receptors of about 100 and 18 %, respectively, could be counteracted by the antiepileptic drug. In this region, partially compensatory effects of gabapentin in bicuculline cotreated cultures could be detected. Conclusion In this study we have shown that bicuculline-induced changes of receptor densities in an in vitro model for epilepsy can be partly abolished by treatment with gabapentin. The balancing of the receptor densities for glutamate and GABA, the most important transmitters in the hippocampus, by gabapentin underlines its suitability for drug therapy in epilepsy.