Preischemic But Not Postischemic Zinc Protoporphyrin Treatment Reduces Infarct Size and Edema Accumulation After Temporary Focal Cerebral Ischemia in Rats

Abstract

Zinc protoporphyrin (ZnPP) has multiple actions. It is an interleukin-1 antagonist as well as a hemeoxygenase inhibitor. Interleukin-1 is produced in ischemic brain and probably contributes to ischemic injury, although the role of heme oxygenase during ischemia is unknown. Whether ZnPP treatment is more effective before or after ischemia, as well as whether it is more protective in permanent or temporary cerebral ischemia, is also unknown. Therefore, we investigated the effect of ZnPP on infarction size and edema in a rodent model of temporary and permanent focal cerebral ischemia. Two groups of adult male Sprague-Dawley rats were pretreated with either 50 mg/kg ZnPP IP or saline and subjected to permanent middle cerebral artery occlusion 30 minutes later. Four additional groups of animals were subjected to 2 hours of temporary middle cerebral artery occlusion followed by 22 hours of reperfusion. Two of these groups were pretreated 30 minutes before middle cerebral artery occlusion with either 50 mg/kg ZnPP IP or saline. The other groups received ZnPP at either 2 or 4 hours after middle cerebral artery occlusion. Regional cerebral blood flow in the ischemic cortex was monitored with laser Doppler flowmetry. Cerebral infarct size and brain water were measured 24 hours after the onset of either form of ischemia. Regional cerebral blood flow after occlusion was approximately 13% to 20% of baseline after either permanent or temporary ischemia. ZnPP had no effect on regional cerebral blood flow, infarct size, or edema formation in permanent ischemia. In contrast, pretreatment significantly reduced infarct size (17.2 +/- 6.6% in controls versus 6.2 +/- 2.9% in pretreated rats) and edema formation (center zone, 4.00 +/- 0.71% water in controls versus 1.18 +/- 0.26% water in pretreated rats) in the model of temporary ischemia, but treatment after occlusion had no effect. ZnPP treatment protected the brain when administered early in the temporary ischemia model.