Postischemic treatment (2-4 h) with anti-CD11b and anti-CD18 monoclonal antibodies are neuroprotective after transient (2 h) focal cerebral ischemia in the rat.
We investigated the effects of F(ab')2 fragments of anti-CD11b and anti-CD18 monoclonal antibodies on ischemic cell damage in the rat when administered upon reperfusion and at 2 h of reperfusion after transient (2 h) middle cerebral artery (MCA) occlusion. 2 h of MCA occlusion was induced by intraluminal insertion of a monofilament. The following groups of animals were investigated. Anti-CD11b groups (n = 15): an intact anti-CD11b antibody (1B6c) and an anti-CD11b F(ab')2 fragment of 1B6c were infused upon reperfusion (4 mg/kg i.v.). Anti-CD18 group (n = 8): an anti-CD18 F(ab')2 fragment of CL26 was infused upon reperfusion (2 mg/kg i.v.), and at 22 h of reperfusion (1 mg/kg i.v.). Anti-CD11b delayed group (n = 9): an anti-CD11b F(ab')2 fragment of 1B6c was infused at 2 h of reperfusion (4 mg/kg i.v.), and at 22 h after reperfusion (2 mg/kg i.v.). Control groups (n = 18): an isotype-matched control antibody (mouse IgG1) was administered: (a) upon reperfusion (n = 13), and (b) at 2 h and 22 h of reperfusion (n = 5). Rats were sacrificed at 7 days of reperfusion. In a separate population of rats subjected to 2 h of MCA occlusion (n = 9), brain myeloperoxidase (MPO) activity was measured at 46 h of reperfusion. The vehicle groups had infarct volumes of 35.21 +/- 2.82% to 41.39 +/- 2.73% of the contralateral hemisphere, respectively. Infarct volume was significantly reduced after treatment with: the intact anti-CD11b antibody upon reperfusion (19.0 +/- 6.6%) (P < 0.05), the fragments of mAbs of anti-CD11b administered upon reperfusion (19.7 +/- 2.7%) (P < 0.05), and at 2 h of reperfusion (22.2 +/- 4.8%) (P < 0.05), and anti-CD18 administered upon reperfusion (20.4 +/- 4.8%) (P < 0.05). Anti-CD11b treatment significantly (P < 0.05) inhibited the increase of MPO activity in the ischemic hemisphere. Our data demonstrate that anti-CD11b and anti-CD18 mAb fragments significantly reduce infarct volume and inhibit the increase of MPO activity in the ischemic lesion; administration of anti-CD11b mAb fragment even at 2 h of reperfusion significantly reduces infarct volume. These data support importance of the beta 2 integrin CD11b/CD18 in ischemia/reperfusion injury and indicate that the therapeutic window for intervention to reduce ischemic cell damage in this model is at least 4 h from the onset of MCA occlusion.
Zhang
Z G
ZG
Department of Neurology, Henry Ford Health Science Center, Henry Ford Hospital, Detroit, MI 48202, USA.
Chopp
M
M
Tang
W X
WX
Jiang
N
N
Zhang
R L
RL
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000918:Antibody Specificity; D001921:Brain / Q000201:enzymology; D018821:CD18 Antigens / Q000276:immunology*; D002546:Ischemic Attack, Transient / Q000628:therapy*; D007958:Leukocyte Count; D016177:Macrophage-1 Antigen / Q000276:immunology*; D008297:Male; D018696:Neuroprotective Agents / Q000276:immunology / Q000627:therapeutic use*; D009195:Peroxidase / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors
D000911:Antibodies, Monoclonal; D018821:CD18 Antigens; D016177:Macrophage-1 Antigen; D018696:Neuroprotective Agents; D009195:Peroxidase