A study on effects of fosphenytoin, a sodium channel blocker, on the post-ischemic rat hippocampus

Cardiac arrest induced transient global ischemia can lead to severe damage in specific brain regions such as the hippocampus. The pathogenesis of this selective neuronal damage has been linked to altered ion homeostasis. Fosphenytoin (FP) is a water-soluble prodrug of phenytoin, an anti-epileptic drug and a voltage dependent sodium channel blocker. In this study, the potential neuroprotective property of FP was examined using a cardiac arrest induced transient global ischemia (TGI) rat model developed by Reid et al . 1996.; Neuronal survival and glial responses in the hippocampal CA1 region were examined after TGI with and without FP treatment. In the dose response study, FP was given i.m. 5 minutes after TGI and resuscitation in doses of 0, 15, 30 and 60 mg/kg. The animals were terminated 7 or 21 days later. Following animal termination, formalin-fixed brains were vibratome sectioned coronally for further processing. An initial impression of the extent of neuronal damage was obtained using a silver impregnation stain. Quantitative data regarding neuronal survival was collected and tabulated from toluidine blue stained 1mum thick plastic sections. Astroglial response was quantified by optical density measurement of CA1 region immunolabeled with glial fibrillary acidic protein (GFAP). Lastly, microglia identified by their nuclear morphology were tabulated from toluidine blue stained semi-thin sections.; Both 30 mg/kg and 60 mg/kg fosphenytoin treatment appeared to be equally effective in protecting hippocampal CA1 pyramidal neurons following a single episode of TGI. Similar protection was found in animals terminated on days 7 and 21. TGI significantly increased astroglial GFAP immunolabeling compared to sham controls, and FP did not alter this response. The microglial cell subset of the CA1 region increased after TGI in both 7-day and 21-day groups. This microglia proliferation was suppressed by post-ischemic FP treatment resulting in a significant reduction of microglial population by 21 days.; This study demonstrates for the first time that post-ischemic FP treatment is effective in attenuating neuronal damage caused by transient global ischemia. Although the precise mechanism of action for this effect remains to be established, it may involve a membrane stabilizing effect via sodium channel modulation of ischemic neurons. An inhibition of microglia activation or migration may also contribute to the neuronal survival. The recently introduced concept of astroglia-neuronal coupling and the finding of a stable astroglial response after TGI and FP treatment invites further analysis of this compound as a neuroprotectant.