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

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.

Download full-text


Available from: Daniel Laskowitz, Sep 28, 2015
18 Reads
    • "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] "
    [Show abstract] [Hide abstract]
    ABSTRACT: Background: 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. Materials and Methods: Male Sprague Dawley rats (300-350 g) were assigned to 3 experimental groups (n = 6 per group): (1) Normotensive rats (N), (2) HS rats and (3) HS rats treated with AG (HS-AG). Rats were hemorrhaged over 60 min to reach a mean arterial blood pressure of 40 mmHg. Rats were treated with 1 ml of 60 mg/kg AG intra-arterially after 60 min HS. Resuscitation was performed in vivo by the reinfusion of the shed blood for 30 min to restore normo-tension. Biopsy samples were taken for light and electron microscopy. Results: Histological examination of hemorrhagic shocked untreated rats revealed structural damage. Less histological damage was observed in multiple organs in AG-treated rats. AG-treatment decreased the number of inflammatory cells and mitochondrial swollen in myocardial cells. Conclusion: AG treatment reduced microscopic damage and injury in multiple organs in a HS model in rats.
    Journal of Emergencies Trauma and Shock 07/2014; 7(3):190-5. DOI:10.4103/0974-2700.136864
  • Source
    • "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: "
    [Show abstract] [Hide abstract]
    ABSTRACT: Intracerebral hemorrhage (ICH) is a devastating stroke subtype characterized by a prominent neuroinflammatory response. Antagonism of pro-inflammatory cytokines by specific antibodies represents a compelling therapeutic strategy to improve neurological outcome in patients after ICH. To test this hypothesis, the tumor necrosis factor alpha (TNF-alpha) antibody CNTO5048 was administered to mice after ICH induction, and histological and functional endpoints were assessed. Using 10 to 12-week-old C57BL/6J male mice, ICH was induced by collagenase injection into the left basal ganglia. Brain TNF-alpha concentration, microglia activation/macrophage recruitment, hematoma volume, cerebral edema, and rotorod latency were assessed in mice treated with the TNF-alpha antibody, CNTO5048, or vehicle. After ICH induction, mice treated with CNTO5048 demonstrated reduction in microglial activation/macrophage recruitment compared to vehicle-treated animals, as assessed by unbiased stereology (P = 0.049). This reduction in F4/80-positive cells was associated with a reduction in cleaved caspase-3 (P = 0.046) and cerebral edema (P = 0.026) despite similar hematoma volumes, when compared to mice treated with vehicle control. Treatment with CNTO5048 after ICH induction was associated with a reduction in functional deficit when compared to mice treated with vehicle control, as assessed by rotorod latencies (P = 0.024). Post-injury treatment with the TNF-alpha antibody CNTO5048 results in less neuroinflammation and improved functional outcomes in a murine model of ICH.
    Journal of Neuroinflammation 08/2013; 10(1):103. DOI:10.1186/1742-2094-10-103 · 5.41 Impact Factor
  • Source
    • "APOE*4 has been shown to augment injury and worsen outcome in various models of neurodegeneration, including cerebral hemorrhage [20], traumatic brain injury (TBI) [21], stroke [8,11,22] and global brain ischemia [23], and has been suggested to be a significant risk factor for cognitive impairment in the early phase after stroke [24]. We assessed the contribution of ApoE4 to the outcome of focal brain ischemia in aged mice maintained on a HF diet and show for the first time that ApoE4 together with long-term intake of a HF diet containing 5.3 times more fat and having 1.5 times higher energy density compared with normal chow leads to significant sensorimotor deficits as analyzed by an adhesive removal test. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Numerous clinical trials in stroke have failed, most probably partially due to preclinical studies using young, healthy male rodents with little relevance to the heterogenic conditions of human stroke. Co-morbid conditions such as atherosclerosis and infections coupled with advanced age are known to contribute to increased risk of cerebrovascular diseases. Clinical and preclinical studies have shown that the E4 allele of human apolipoprotein (ApoE4) is linked to poorer outcome in various conditions of brain injury and neurodegeneration, including cerebral ischemia. Since ApoE is a known regulator of lipid homeostasis, we studied the impact of a high-cholesterol diet in aged mice in the context of relevant human ApoE isoforms on the outcome of focal brain ischemia. Aged mice expressing human E3 and E4 isoforms of ApoE in C57BL/6J background and C57BL/6J mice fed on either a high-fat diet or a normal diet underwent permanent middle cerebral artery occlusion. The impact of a high-cholesterol diet was assessed by measuring the serum cholesterol level and the infarction volume was determined by magnetic resonance imaging. Sensorimotor deficits were assessed using an adhesive removal test and the findings were correlated with inflammatory markers. We show that expression of human ApoE4 renders aged mice fed with a western-type diet more susceptible to sensorimotor deficits upon stroke. These deficits are not associated with atherosclerosis but are accompanied with altered astroglial activation, neurogenesis, cyclooxygenase-2 immunoreactivity and increased plasma IL-6. Our results support the hypothesis that ApoE alleles modify the inflammatory responses in the brain and the periphery, thus contributing to altered functional outcome following stroke.
    Journal of Neuroinflammation 08/2013; 10(1):102. DOI:10.1186/1742-2094-10-102 · 5.41 Impact Factor
Show more