Fosphenytoin reduces hippocampal neuronal damage in rat following transient global ischemia

Fosphenytoin, a water-soluble disodium phosphate ester of phenytoin, is a phenytoin prodrug with similar anticonvulsant properties. In this study, we evaluated its neuroprotective properties in a cardiac arrest-induced global ischemia model. After 12 minute ischemia, Long-Evans hooded rats were resuscitated, given fosphenytoin (30 mg/kg, i.m.) or saline 5 minutes after the ischemic episode, and killed on day 7. Brains were removed, fixed, and vibratome sectioned to assess the numbers of normal appearing CAI pyramidal neurons and for immunohistological staining of glial fibrillary acidic protein (GFAP). After global ischemia, the number of hippocampal CAI pyramidal neurons decreased significantly (from 14.33 +/- 1.73 to 2.19 +/- 0.16 per 100 mu m(2)). Most hippocampal CAI pyramidal neurons showed signs of injury and GFAP immunoreactivity of the region increased. With fosphenytoin treatment 5 min after ischemia, hippocampal CAI pyramidal neurons remained at near control level (13.90 +/- 0.92), however, GFAP staining was not significantly changed. Our data, although indicating different neuronal and glial responses following fosphenytoin treatment, nevertheless, suggest that fosphenytoin is an effective neuroprotectant against ischemia-induced damage.