Caspase inhibitors are functionally neuroprotective against oxygen glucosedeprivation induced CA1 death in rat organotypic hippocampal slices

We have explored the neuroprotective efficacy of the cell penetrant caspase inhibitor, Ac-YVAD-cmk, in a hippocampal slice model of neuronal cell deat h induced by oxygen and glucose deprivation. Organotypic hippocampal slice cultures were prepared from 8 to 10-day-old rats and maintained for 10 to 1 2 days in vitro. Pre-treatment with Ac-YVAD-cmk prior to 45 mill oxygen and glucose deprivation was neuroprotective as measured by propidium iodide up take, with an EC50 between 1 and 10 mu mol/l. Ac-YVAD-cmk was also able to preserve synaptic function in the organotypic hippocampal slice cultures 24 h after oxygen and glucose deprivation. Ac-YVAD-cmk prevented the increase in histone-associated DNA fragmentation induced by oxygen and glucose depr ivation. Interleukin-1 beta did not reverse the protective effect of Ac-YVA D-cmk, and interleukin-1 receptor antagonist alone was not protective. Thes e results show that caspase inhibitors are neuroprotective in a hippocampal slice culture system, using structural, biochemical and electrophysiologic al endpoints, and that this effect is not a result of inhibition of interle ukin-1 beta production. (C) 2000 Elsevier Science B.V. All rights reserved.