Raymond F. Regan, PhD

Contact Dr. Regan

900 Walnut St.

Philadelphia, PA 19107

(215) 955-6844
(215) 923-6225 fax

What Causes Cell Injury After Intracerebral Hemorrhage?

The aim of our research is to define the molecular mechanisms that contribute to the death of CNS cells after an intracerebral hemorrhage (ICH), a type of stroke that has a very high morbidity and mortality and, currently, very limited treatment options. For many years, injury after ICH was attributed to the mass effect of the hematoma, which presumably caused ischemia by compressing adjacent tissue, impeding blood flow. However, over the past decade, regional blood flow and oxygen extraction studies have often failed to demonstrate ischemia in this tissue, even after large hemorrhages associated with considerable morbidity and mortality. An alternate hypothesis, which is the current focus of our research, is that toxins released from the hematoma may contribute to injury to surrounding tissue. Our laboratory is particularly interested in the oxidative injury produced by hemoglobin, which is the most abundant protein in blood. After its release by lysed erythrocytes, the heme moieties of hemoglobin are broken down to iron, carbon monoxide, and biliverdin in a reaction catalyzed by the heme oxygenase enzymes. Neurons appear to be particularly vulnerable to hemoglobin, perhaps due to their very limited ability to sequester and detoxify iron.

We use both cell culture and in vivo models. Primary neuron and astrocyte cultures are used to test the effect of gene knockout or gene transfer on cell vulnerability to hemoglobin and other oxidants. They are also used for pharmacologic screening.In vivo, ICH is modeled by stereotactic injection of either autologous blood or collagenase into the mouse striatum; the latter produces a hemorrhage by disrupting local blood vessels. Methods in common use include immunoblotting, fluorescence imaging, and assays to detect protein oxidation, lipid oxidation, and cell viability.

Our ultimate goal is to develop novel therapies for ICH that minimize cell injury and neurologic deficits

Publications

Most recent Peer-reviewed Publications

1. Effect of Iron Chelators on Methemoglobin and Thrombin Preconditioning
2. Hemopexin decreases hemin accumulation and catabolism by neural cells
3. Iron accumulation and neurotoxicity in cortical cultures treated with holotransferrin
4. Increased striatal injury and behavioral deficits after intracerebral hemorrhage in hemopexin knockout mi Laboratory investigation
5. Apotransferrin protects cortical neurons from hemoglobin toxicity
6. Accelerated hemolysis and neurotoxicity in neuron-glia-blood clot co-cultures
7. Iron regulatory protein-2 knockout increases perihematomal ferritin expression and cell viability after intracerebral hemorrhage
8. Heme oxygenase-2 deletion causes endothelial cell activation marked by oxidative stress, inflammation, and angiogenesis
9. Minocycline attenuates iron neurotoxicity in cortical cell cultures
10. Increasing expression of H- or L-ferritin protects cortical astrocytes from hemin toxicity
11. Heme oxygenase activity and hemoglobin neurotoxicity are attenuated by inhibitors of the MEK/ERK pathway
12. Exacerbated corneal inflammation and neovascularization in the HO-2 null mice is ameliorated by biliverdin
13. Neurons lacking iron regulatory protein-2 are highly resistant to the toxicity of hemoglobin
14. Hemoglobin neurotoxicity is attenuated by inhibitors of the protein kinase CK2 independent of heme oxygenase activity
15. Carbon monoxide donors or heme oxygenase-1 (HO-1) overexpression blocks interleukin-18-mediated NF-κB-PTEN-dependent human cardiac endothelial cell death
16. Time course of increased heme oxygenase activity and expression after experimental intracerebral hemorrhage: Correlation with oxidative injury
17. Astrocyte-specific heme oxygenase-1 hyperexpression attenuates heme-mediated oxidative injury
18. Interactions between NO, CO and an endothelium-derived hyperpolarizing factor (EDHF) in maintaining patency of the ductus arteriosus in the mouse
19. H-ras Inhibits RhoA/ROCK Leading to a Decrease in the Basal Tone in the Internal Anal Sphincter
20. Attenuation of oxidative injury after induction of experimental intracerebral hemorrhage in heme oxygenase-2 knockout mice

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