Neutrophils contribute to intracerebral haemorrhages after treatment with recombinant tissue plasminogen activator following cerebral ischaemia

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Abstract
Background and purpose:  Polymorphonuclear neutrophils (PMNs) contribute to the vascular damage caused by transient cerebral ischaemia. Here we have evaluated the role of PMNs in intracerebral haemorrhage (ICH) induced in a model of thrombolysis with recombinant tissue plasminogen activator (t‐PA) during the acute phase of cerebral ischaemia.Experimental approach:  The middle cerebral artery (MCA) of male spontaneously hypertensive rats was occluded for 1 h followed by reperfusion and, 5 h later, infusion of thrombolytic products (generated in vitro by t‐PA on autologous clots). Effects of pretreatment (before the MCA occlusion) with vinblastine (4 days before; 0.5 mg·kg−1), monoclonal anti‐neutrophil antibody (mAbRP3; 12 h, 0.3 mg·kg−1) or saline on ICH, neutrophil infiltration, MCA vascular reactivity and brain infarct volume were assessed, 24 h after the beginning of reperfusion.Key results:  Depletion of circulating neutrophils significantly reduced t‐PA‐induced ICH (vinblastine, 4.6 ± 1.0; mAbRP3, 5.2 ± 1.0 vs. saline, 10.8 ± 2.7 haemorrhages; P < 0.05). This depletion was associated with a decrease in cerebral infiltration by neutrophils and a decrease of endothelium‐dependent, vascular dysfunction in isolated MCA, induced by the ischaemia/reperfusion and t‐PA treatment. Brain infarct volume was significantly decreased after vinblastine treatment (159 ± 13 mm3 vs. 243 ± 16 mm3 with saline; P < 0.01) but not after depletion with mAbRP3 (221 ± 22 mm3).Conclusions and implications:  Our results showed that pharmacological depletion of PMNs prevented t‐PA‐induced ICH, in parallel with a decrease in cerebral infiltration by PMNs and a decreased endothelial dysfunction in cerebral blood vessels.Mandarin translation of

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