Pathological significance of the neutrophil in focal cerebral ischemia.

摘要

Using a focal cerebral ischemic model in the rat, the time course of neutrophil infiltration was studied by the enzymatic assay of the activity of myeloperoxidase, a marker enzyme of neutrophils, in the ischemic cortex.; The involvement of reactive oxygen radicals in ischemic brain injury is suggested by the following findings: (1) The administration of polyethylene glycol (PEG) conjugated superoxide dismutase (SOD) and catalase (CAT), which scavenge superoxide and hydrogen peroxide respectively, reduces ischemic brain injury. Intravenous administration of PEG-SOD (10,000 U/kg) and PEG-CAT (10,000 U/kg) before ischemia reduced the infarct volume (treatment: 139 {dollar}pm{dollar} 9 mm{dollar}sp3{dollar}, n = 38; placebo: 182 {dollar}pm{dollar} 8 mm{dollar}sp3{dollar}, n = 37, p {dollar}<{dollar} 0.002). (2) The content of endogenous antioxidative enzymes was reduced following focal cerebral ischemia and reperfusion. Superoxide dismutase, catalase, and glutathione peroxidase activity declined in a time dependent manner in the ischemic cortex. The levels of SOD, CAT and GSH-px activity decreased in a time-dependent manner in the ischemic regions during reperfusion. The significant reduction of these enzymes' activity during reperfusion might compromise the brain's ability to defend against the toxic effects of reactive oxygen metabolites. (3) Animals pretreated with allopurinol, which inhibits xanthine oxidase, also have smaller infarcts.; Indirect findings in this study do suggest the roles of neutrophils in ischemic injury and include: (a) neutropenia induced by methotrexate (MTX) reduces infarct size significantly (control: 157.9 {dollar}pm{dollar} 13.6 mm{dollar}sp3{dollar}, n = 17; MTX: 56.7 {dollar}pm{dollar} 16.4 n = 8); (b) ibuprofen, which inhibits arachidonic acid metabolism and neutrophil function, reduces infarct size (control: 157.9 {dollar}pm{dollar} 13.6 mm{dollar}sp3{dollar}, n = 17; ibuprofen: 76.3 {dollar}pm{dollar} 11.8 mm{dollar}sp3{dollar}, n = 20, p {dollar}<{dollar} 0.001).; The contribution of arachidonic acid metabolism to ischemic brain injury was supposed by the following observation: arachidonic acid metabolites increase in a time-dependent manner during reperfusion.; Several issues arising from this study remain to be clarified and described below: (1) The evolution of post-ischemic brain edema and the increase in vascular permeability correspond to neutrophil infiltration in a time-course study. This finding raises the possibility that post-ischemic inflammatory processes including neutrophil infiltration may contribute to the pathogenesis of ischemic brain edema. (2) More specific implication of the roles of neutrophils in the pathogenesis of ischemic brain injury awaits the further development of pharmacological and immunological tools, such as drugs or antibodies which specifically block neutrophil activations.; Overall, results from this study reveal a post-ischemic neutrophil infiltration following focal ischemic reperfusion. (Abstract shortened with permission of author.)