Differential Hydroxylation of Salicylate in Core and Penumbra Regions During Focal Reversible Cerebral Ischemia

Abstract

Background and PurposeFree radical-mediated damage during and/or after cerebral ischemia is thought to participate in the elaboration of stroke-related injury. To elucidate the role of this mechanism in cerebral damage, the study presented herein sought to clarify the spatial and temporal features of the free radical response to transient ischemia. With use of a reproducible model of in vivo focal ischemia/reperfusion, the time course of salicylate hydroxylation was measured in ischemic core and penumbra regions.MethodsTransient focal cerebral ischemia was produced in Sprague-Dawley rats by occluding both carotid arteries and one middle cerebral artery for 3 hours, followed by reperfusion. Cerebral reperfusion was confirmed by visual inspection and iodo[14C]antipyrine autoradiography. A microdialysis probe was placed stereotactically in either the ischemic core or ischemic penumbra of the frontoparietal cortex; the probe was perfused with salicylate, and dialysate samples were analyzed by high-performance liquid chromatography for salicylate hydroxylation products.ResultsSalicylate hydroxylation was significantly increased during ischemia and was further increased during 6 hours of reperfusion in the penumbra compared with sham controls. In comparison, a delayed increase in hydroxylation was observed within the ischemic core region only after 3 hours of reperfusion.ConclusionA differential generation of salicylate hydroxylation occurs in core and penumbra regions in association with focal ischemia/reperfusion of the rat neocortex. The early and progressive response in the penumbra suggests that free radical mechanisms may be continuously active in the aggravation of injury in the ischemic penumbra during ischemia and reperfusion. In contrast, the relatively delayed onset of hydroxylation in the core region indicates that this mechanism participates primarily in the late stages of ischemic injury in densely ischemic tissue. These findings are consistent with the concept that the role of free radicals in cerebral injury may differ qualitatively and/or quantitatively in areas of total and partial cerebral perfusion.