Cycloheximide reduces infarct volume when administered up to 6 h after mild focal ischemia in rats

We have previously described a rodent model of brief (30 min) middle cerebr al artery occlusion followed by reperfusion, in which infarction develops g radually. reaching completion more than 3 days after ischemia, accompanied by morphological, biochemical, and pharmacological evidence of apoptosis. I n the present study, we tested the hypotheses that delayed administration o f a protein synthesis inhibitor would be effective in reducing tissue injur y in this slowly evolving ischemic infarction, and that efficacy of this tr eatment would wane with more prolonged ischemia. Focal cerebral ischemia wa s induced in Long-Evans rats by occlusion of the right middle cerebral arte ry. Infarction volume was analyzed using triphenyl tetrazolium chloride sta ining, and morphology was studied using hematoxylin and eosin stained secti ons. Following 30 min middle cerebral artery occlusion and reperfusion, the core ischemic region exhibited vacuolization in the neuropil by 36 h after ischemia, and infarction reached full size by 7 days after ischemia. Cyclo heximide reduced infarct volume when given up to 6 h after ischemia. If the duration of ischemic insult was increased to 90 min, the therapeutic windo w for delayed cycloheximide was only 30 min. In permanent middle cerebral a rtery occlusion, cycloheximide was ineffective even when given prior to isc hemia onset. After mild, but not severe, ischemic insults, cerebral infarct ion develops slowly and may be treatable with protein synthesis inhibitors, even when treatment is delayed for up to 6 h after the onset of ischemia. (C) 2001 Elsevier Science B.V. All rights reserved.