Antibody to the alpha4 integrin decreases infarct size in transient focal cerebral ischemia in rats.
OBJECTIVE
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.
Becker
K
K
University of Washington School of Medicine, Seattle, USA. kjb@u.washington.edu
Kindrick
D
D
Relton
J
J
Harlan
J
J
Winn
R
R
D000818:Animals; D000906:Antibodies / Q000494:pharmacology*; D015703:Antigens, CD / Q000276:immunology* / Q000378:metabolism; D001831:Body Temperature / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D015815:Cell Adhesion Molecules / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D002544:Cerebral Infarction / Q000209:etiology / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D020244:Infarction, Middle Cerebral Artery / Q000150:complications; D039441:Integrin alpha4; D002546:Ischemic Attack, Transient / Q000209:etiology / Q000276:immunology* / Q000378:metabolism; D007958:Leukocyte Count; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology; D008297:Male; D009000:Monocytes / Q000187:drug effects / Q000276:immunology; D051381:Rats; D011917:Rats, Inbred Lew; D016201:Receptors, Lymphocyte Homing / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D016896:Treatment Outcome
D000906:Antibodies; D015703:Antigens, CD; D015815:Cell Adhesion Molecules; D016201:Receptors, Lymphocyte Homing; D039441:Integrin alpha4