Pharmacogenomic Effects of Apolipoprotein E on Intracerebral Hemorrhage

Department of Anesthesiology, Duke University Medical Center, Durham, NC 27710, USA.
Stroke (Impact Factor: 5.72). 02/2009; 40(2):632-9. DOI: 10.1161/STROKEAHA.108.530402
Source: PubMed


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.
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.
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.
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.

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    • "L-arginine derivatives, such as L-NMMA and L-NAME, inhibit nitric oxide synthase and increase the survival rate following HS in rats.[1112] aminoguanidine (AG) is a more potent NOS inhibitor than L-NMMA and L-NAME.[131415] AG treatment delays the circulatory failure following septic shock in rats and improves survival in a murine model of septic shock.[1516] "
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    • "These time points for administration and outcome measurements were chosen based on prior work with promising therapeutics and neuroinflammatory metrics [7,10,12-14]. Sham animals were not included in these experiments as prior work demonstrates that they behave like uninjured animals [7,10,13,14]. Separate observers (HND, BL, BRW), blinded to treatment group, assessed five separate cohorts of mice as follows: "
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