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(Stroke. 2009;40:632.)
© 2009 American Heart Association, Inc.

Original Contributions

Pharmacogenomic Effects of Apolipoprotein E on Intracerebral Hemorrhage

Michael L. James, MD; Patrick M. Sullivan, PhD; Christopher D. Lascola, MD, PhD; Michael P. Vitek, PhD Daniel T. Laskowitz, MD

From Department of Anesthesiology (M.L.J., D.T.L.), Department of Medicine (Neurology) (M.L.J., M.P.V., D.T.L.), Department of Medicine (Geriatrics) (P.M.S.), Department of Neurobiology (M.P.V., D.T.L.), Department of Surgery (Neurosurgery) (M.L.J.), Department of Radiology (Neuroradiology) (C.D.L.), Multidisciplinary Neuroprotection Laboratory (M.L.J., C.D.L., D.T.L.), Duke University Medical Center, Durham, NC; Cognosci, Inc (M.P.V.), Morrisville, NC.

Correspondence to Michael L. James, MD, Department of Anesthesiology, Duke University Medical Center, Box 3094, Durham, NC, 27710. E-mail james040{at}mc.duke.edu

Background and Purpose— The purpose of the study was to evaluate the effect of APOE genotype and the feasibility of administering an apolipoprotein E-mimetic therapeutic to modify outcomes in a murine model of intracerebral hemorrhage.

Methods— Intracerebral hemorrhage was induced via stereotactic injection of 0.1 U Clostridial collagenase into the left basal ganglia of wild-type and apolipoprotein-E targeted-replacement mice, consisting of either homozygous 3/3 or 4/4 genotypes. Animals were randomized to receive either vehicle or apolipoprotein E-mimetic peptide. Outcomes included functional neurological tests (21-point neuroseverity score and Rotorod latency) over the initial 7 days after injury, radiographic and histological hemorrhage size at 3 and 7 days, brain water content for cerebral edema at 24 hours, and quantitative polymerase chain reaction for inflammatory markers at 6, 24, and 48 hours.

Results— Apolipoprotein-E targeted-replacement mice consisting of homozygous 3/3 demonstrated superior neuroseverity scores and Rotorod latencies over the first 3 days after intracerebral hemorrhage, decreased cerebral edema at 24 hours, and reduced upregulation of IL-6 and endothelial nitric oxide synthase at 6 hours when compared to their apolipoprotein-E targeted-replacement mice consisting of homozygous 4/4 counterparts. After intravenous administration of 1 mg/kg apolipoprotein E-mimetic peptide, both wild-type and apolipoprotein-E targeted-replacement mice consisting of homozygous 4/4 exhibited improved functional outcomes over 7 days after intracerebral hemorrhage, less edema at 24 hours, and reduced upregulation of IL-6 and endothelial nitric oxide synthase when compared to mice that did not receive the peptide.

Conclusions— Our data indicate that APOE genotype influences neurological outcome after intracerebral hemorrhage in a murine model. In particular APOE4 is associated with poor functional outcome and increased cerebral edema. Additionally, this outcome can be modified by the addition of an apolipoprotein E mimetic-peptide, COG1410.

Key Words: apolipoprotein E • gene therapy • inflammation • intracerebral hemorrhage • mouse