Caspase inhibitors reduce neuronal injury after focal but not global cerebral ischemia in rats

Background and Purpose-Studies show that blocking the activation of caspase s by the caspase inhibitors z-VAD.FMK and z-DEVD.FMK can reduce ischemic ne uronal injury after cerebral ischemia. Because the severity of ischemia was mild in some studies, we tested the efficacy of these caspase inhibitors o n moderately severe but transient forebrain and focal ischemic insults in t he rat. Methods-Various regimens of z-VAD, z-DEVD, and control DMSO were given to r ats subjected to either 4-vessel occlusion ischemia (4-VO, 10-minute occlus ion, 7-day survival) or distal middle cerebral artery occlusion (MCAo, 90-m inute occlusion, 22.5-hour survival). In global ischemia, treatments were g iven immediately after ischemia (experiment I) or as preischemic and postis chemic treatments (experiment 2), Three focal ischemia experiments were don e. Injection times were 60 minutes into ischemia (experiment 1) and 60 minu tes into ischemia plus 30 and 120 minutes after ischemia (experiment 2). Ex periment 3 was identical to experiment 2 except that a 30-minute preischemi a treatment was instituted. Core normothermia was maintained in all experim ents during ischemia. However, in the last focal and global experiments, co re and brain temperatures, respectively, were also measured after ischemia with telemetry probes. Because hyperthermia accompanied z-DEVD treatment, a n extra z-DEVD-treated group (MCAo) was included with temperature clamped a t normothermia, Results-Neither z-VAD nor z-DEVD significantly reduced CA1 injury after glo bal ischemia. In focal ischemia, both drugs significantly reduced infarctio n, but only in the third experiment, and the prevention of hyperthermia tha t accompanied z-DEVD treatment did not alter this. Conclusions-These results suggest a detrimental role of caspases in moderat ely severe focal but not global cerebral ischemia.