Continuous cytosine-b-D-arabinofuranoside infusion reduces ectopic granule cells in adult rat hippocampus with attenuation of spontaneous recurrent seizures following pilocarpine-induced status epilepticus.

Abstract

Brief or prolonged seizures induce various patterns of plasticity. Axonal or dendritic remodelling and development of ectopic granule cells have been described in the hilus and molecular layer of the adult rodent hippocampus. Hippocampal cell proliferation also occurs after seizures. However, whether the seizure-induced cell proliferation plays a pathological or reparative role in the epileptic brain is unknown. In this study, we attempted to suppress the seizure-induced cell proliferation with the antimitotic agent cytosine-b-D-arabinofuranoside (Ara-C) and to examine the development of spontaneous recurrent seizures (SRS). Experimental status epilepticus was induced with pilocarpine, and Ara-C or vehicle alone was infused continuously with an osmotic minipump. SRS were video-monitored. BrdU immunohistochemistry was used for the spatial and temporal analysis of hippocampal cell proliferation, and double labelling with NeuN, calbindin and GFAP antibodies was performed for the differentiation of BrdU-positive cells. Timm staining was also performed for evaluation of mossy fibre sprouting (MFS). With continuous Ara-C infusion, the likelihood of developing SRS was decreased and, during the latent period, the development of ectopic granule cells in the hilus and new glia in the CA1 area was reduced when compared with the vehicle-infused group, while MFS was not altered. The results suggest that the hippocampal cell proliferation plays a pro-epileptogenic role rather than a compensatory role, and that the epileptogenic process may be associated with the generation of new glia in the CA1 area and/or new neurons in the dentate gyrus, particularly the ectopically located hilar granule cells.