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


METHODS
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.


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 mm(3) vs. 243 +/- 16 mm(3) with saline; P < 0.01) but not after depletion with mAbRP3 (221 +/- 22 mm(3)).


CONCLUSIONS
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.
Gautier
Sophie
S
EA1046, Département de Pharmacologie médicale, Institut de Médecine Prédictive et de Recherche Thérapeutique, Université de Lille 2, Faculté de Médecine, Centre Hospitalier Universitaire, Lille, France.
Ouk
Thavarak
T
Petrault
Olivier
O
Caron
Jacques
J
Bordet
Régis
R
D000818:Animals; D002545:Brain Ischemia / Q000097:blood* / Q000150:complications; D002543:Cerebral Hemorrhage / Q000097:blood / Q000139:chemically induced*; D006973:Hypertension / Q000097:blood* / Q000150:complications; D008297:Male; D020556:Neutrophil Infiltration / Q000187:drug effects*; D009504:Neutrophils / Q000166:cytology*; D051381:Rats; D011918:Rats, Inbred SHR; D011994:Recombinant Proteins / Q000009:adverse effects / Q000627:therapeutic use; D013927:Thrombosis / Q000097:blood / Q000150:complications; D010959:Tissue Plasminogen Activator / Q000009:adverse effects* / Q000627:therapeutic use
D011994:Recombinant Proteins; D010959:Tissue Plasminogen Activator