Abstract 2086: Leukocyte Anti-adhesion Therapy Provides Neuroprotection after Transient Global Cerebral Ischemia in the Mouse
Background: The inflammatory response is increasingly recognized as an important mechanism following reperfusion after transient global cerebral ischemia (GCI). Cerebral endothelial cell adhesion receptor mRNA and protein expression have been reported to be increased for several days following GCI.
Hypothesis Blocking leukocyte adhesion to cerebral endothelial cells using a monoclonal antibody to the leukocyte β-2 integrin adhesion receptor (anti-CD18 MAb) would improve neuronal survival, blood brain barrier (BBB) integrity, and functional outcome following GCI.
Methods: Male C57Bl/6 mice were subject to 10 minutes of bilateral occlusion of the common carotid artery (BCCO) or sham operation. Mice were randomized to 4 experimental groups:
BCCO ischemia followed by injections of anti-CD18;
BCCO ischemia followed by injections of isotype matched non-binding control antibody (NBC);
sham surgery followed by injections of anti-CD18; and
sham surgery followed by injections of NBC.
Anti-CD18 or NBC antibodies were injected twice daily for three days beginning immediately following surgery in all groups. Mice were sacrificed at 72-hours, followed by neuropathological examination for hippocampal damage and BBB dysfunction (assessed by fibronectin extravasation). In separate experiments to evaluate memory, mice were trained to locate a submerged platform in a Morris Water Maze, subjected to BCCO or sham, and a probe test performed 7 days later. The mice were then retrained to locate the submerged platform and subjected to a subsequent probe test at 21 days, followed by sacrifice at 4 weeks post-ischemia or sham for neuropathological examination.
Results: No neuronal cell death was seen in sham animals. Cerebral ischemia led to both marked neuronal damage and fibronectin extravasation from the BBB. Anti-CD18 MAb reduced neuronal damage by 65% at 72 hours and by 74% at 4 weeks following ischemia. Animals subject to BCCO ischemia also had significant impairment of memory. Anti-CD18 MAb significantly improved memory in BCCO ischemia animals at both 7 and 21 days following injury.
Conclusion: Anti-CD18 Mab significantly improves hippocampal cell survival, blood-brain barrier integrity, and memory following global cerebral ischemia in the mouse.