Neuroprotection with the CXCL8 inhibitor repertaxin in transient brain ischemia.
Infiltration of polymorphonuclear neutrophils (PMNs) is thought to play a role in ischemic brain damage. The present study investigated the effect of repertaxin, a new noncompetitive allosteric inhibitor for the receptors of the inflammatory chemokine CXC ligand 8 (CXCL8)/interleukin-8 (IL-8), on PMN infiltration and tissue injury in rats. Cerebral ischemia was induced by permanent or transient occlusion of the middle cerebral artery and myeloperoxidase activity, a marker of PMN infiltration, and infarct volume were evaluated 24 h later. Repertaxin (15 mg/kg) was administered systemically at the time of ischemia and every 2 h for four times. In permanent ischemia repertaxin reduced PMN infiltration by 40% in the brain cortex but did not limit tissue damage. In transient ischemia (90-min ischemia followed by reperfusion), repertaxin inhibited PMN infiltration by 54% and gave 44% protection from tissue damage. Repertaxin had anti-inflammatory and neuroprotective effects also when given at reperfusion and even at 2 h of reperfusion. The protective effect of repertaxin did not interfere with brain levels of the chemokine. Since the PMN infiltration and its inhibition by repertaxin were comparable in the two models we conclude that reperfusion induces PMN activation, and inhibition of CXCL8 by repertaxin might be of pharmacological interest in transient ischemia.
Garau
Angela
A
Mario Negri Institute for Pharmacological Research, Milan, Italy.
Bertini
Riccardo
R
Colotta
Francesco
F
Casilli
Federica
F
Bigini
Paolo
P
Cagnotto
Alfredo
A
Mennini
Tiziana
T
Ghezzi
Pietro
P
Villa
Pia
P
D000818:Animals; D001921:Brain / Q000033:anatomy & histology; D002545:Brain Ischemia / Q000188:drug therapy / Q000473:pathology*; D054412:Chemokine CCL8; D007249:Inflammation / Q000188:drug therapy / Q000473:pathology / Q000517:prevention & control; D002546:Ischemic Attack, Transient / Q000188:drug therapy / Q000473:pathology; D008297:Male; D018945:Monocyte Chemoattractant Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D051381:Rats; D015427:Reperfusion Injury / Q000473:pathology; D013449:Sulfonamides / Q000494:pharmacology*; D013997:Time Factors
D054412:Chemokine CCL8; D018945:Monocyte Chemoattractant Proteins; D018696:Neuroprotective Agents; D013449:Sulfonamides; C490707:reparixin