Antibody to the alpha4 integrin decreases infarct size in transient focal cerebral ischemia in rats

Abstract

Background and purpose: Inflammation, a process that involves neutrophils, lymphocytes, and monocytes, contributes to cerebral ischemic injury. Blockade of neutrophil adhesion to endothelium improves outcome after experimental stroke. In this study we sought to assess the contribution of lymphocytes and monocytes to ischemic brain injury.

Methods: Male Lewis rats underwent 3 hours of middle cerebral artery occlusion followed by 45 hours of reperfusion. Two hours after the onset of ischemia, one group of animals received an intraperitoneal injection of antibodies to the alpha(4) integrin (n=16); another group was injected with an isotype control antibody (n=11). Neurological examination, body temperature, and body weight were assessed at different time points after stroke. Animals were killed 48 hours after the onset of ischemia for determination of infarct volume and leukocyte counts.

Results: There were no significant differences in body temperature or weight at any time. Neurological scores (deficits) were significantly less in animals treated with anti-alpha(4) antibodies at 24 (2.0+/-1.2 versus 3. 0+/-0.4; P:=0.006) and 48 (2.0+/-1.2 versus 3.0+/-0.8; P:=0.011) hours after ischemia. Peripheral blood leukocyte counts were significantly higher in anti-alpha(4)-treated animals (6.8+/-2.2 x 10(9) versus 2.9+/-1.9 x 10(9); P:=0.001) and revealed a lymphocyte/monocyte predominance (86.0+/-16.2% versus 71.0+/-15.6%; P:=0.008). Infarct volume was significantly less in animals treated with antibodies to alpha(4) (120.1+/-51.21 versus 173.7+/-42.29 mm(3); P:=0.012).

Conclusions: These data support a role for lymphocytes and monocytes in cerebral ischemic injury and show that blockade of alpha(4), even when instituted after the onset of ischemia, can improve neurological outcome and decrease infarct volume.