The dose-response relationship and therapeutic window for dizocilpine (MK-801) in a rat focal ischaemia model.

The purpose of the present study was to examine the dose-response relationship and the maximum time for which effective therapy could be delayed for the N-methyl-D-aspartate antagonist dizocilpine (MK-801) as a neuroprotective agent in a permanent focal ischaemia model in the rat. The ED50 for dizocilpine in the amelioration of cortical damage in this model was found to be approximately 0.3 mg/kg (single i.p. dose, 30 min post onset of ischaemia) and significant protection was only obtained when therapy (3 mg/kg i.p.) was delayed for one hour or less after the onset of ischaemia. In a further experiment, dizocilpine 3 mg/kg i.p., produced a peak plasma level of 44 ng/ml and had a t1/2 elimination of 1.65 h.