Article

Pharmacogenomic effects of apolipoprotein e on intracerebral hemorrhage.

Department of Anesthesiology, Duke University Medical Center, Durham, NC 27710, USA.
Stroke (Impact Factor: 6.02). 01/2009; 40(2):632-9. DOI: 10.1161/STROKEAHA.108.530402
Source: PubMed

ABSTRACT 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.

0 Bookmarks
 · 
90 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Although intracerebral hemorrhage (ICH) is a common form of cerebrovascular disease, little is known about factors leading to neurological deterioration occurring beyond 48 h after hematoma formation. The purpose of this study was to characterize the incidence, consequences, and associative factors of late neurological deterioration (LND) in patients with spontaneous ICH. Using the Duke University Hospital Neuroscience Intensive Care Unit database from July 2007 to June 2012, a cohort of 149 consecutive patients with spontaneous supratentorial ICH met criteria for analysis. LND was defined as a decrease of two or more points in Glasgow Coma Scale score or death during the period from 48 h to 1 week after ICH symptom onset. Unfavorable outcome was defined as a modified Rankin Scale score of >2 at discharge. Forty-three subjects (28.9 %) developed LND. Logistic regression models revealed hematoma volume (OR = 1.017, 95 % CI 1.003-1.032, p = 0.019), intraventricular hemorrhage (OR = 2.519, 95 % CI 1.142-5.554, p = 0.022) and serum glucose on admission (OR = 2.614, 95 % CI 1.146-5.965, p = 0.022) as independent predictors of LND. After adjusting for ICH score, LND was independently associated with unfavorable outcome (OR = 4.000, 95 % CI 1.280-12.500, p = 0.017). In 65 subjects with follow-up computed tomography images, an increase in midline shift, as a surrogate for cerebral edema, was independently associated with LND (OR = 3.822, 95 % CI 1.157-12.622, p = 0.028). LND is a common phenomenon in patients with ICH; further, LND appears to affect outcome. Independent predictors of LND include hematoma volume, intraventricular hemorrhage, and blood glucose on admission. Progression of perihematomal edema may be one mechanism for LND.
    Neurocritical Care 08/2013; · 3.04 Impact Factor
  • Clinical Lipidology 10/2013; 8(5):561-571. · 0.86 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Nitric oxide (NO) has been shown to increase following hemorrhagic shock (HS). Peroxynitrite is produced by the reaction of NO with reactive oxygen species, leads to nitrosative stress mediated organ injury. We examined the protective effects of a potent inhibitor of NO synthase, aminoguanidine (AG), on myocardial and multiple organ structure in a rat model of HS.
    Journal of Emergencies Trauma and Shock 07/2014; 7(3):190-5.

Full-text (2 Sources)

Download
34 Downloads
Available from
May 21, 2014