Pharmacogenomic effects of apolipoprotein e on intracerebral hemorrhage.
OBJECTIVE
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.
James
Michael L
ML
Department of Anesthesiology, Duke University Medical Center, Durham, NC 27710, USA. james040@mc.duke.edu
Sullivan
Patrick M
PM
Lascola
Christopher D
CD
Vitek
Michael P
MP
Laskowitz
Daniel T
DT
D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics*; D001479:Basal Ganglia; D002543:Cerebral Hemorrhage / Q000139:chemically induced / Q000188:drug therapy* / Q000235:genetics*; D008279:Magnetic Resonance Imaging; D051379:Mice; D008822:Mice, Transgenic; D003012:Microbial Collagenase; D008845:Microinjections; D009422:Nervous System Diseases / Q000523:psychology; D010455:Peptides / Q000494:pharmacology; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic; D004856:Postural Balance / Q000187:drug effects / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013238:Stereotaxic Techniques; D016896:Treatment Outcome
D001057:Apolipoproteins E; D010455:Peptides; D003012:Microbial Collagenase