Protective effect of astrocyte heme oxygenase-1 after intracerebral hemorrhage

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Project Summary/Abstract Intracerebral hemorrhage (ICH) is the primary event in about 10% of strokes, and has high morbidity and mortality rates. In addition to its mass effect, experimental evidence indicates that release of toxins such as hemoglobin from the hematoma contributes to cell loss in adjacent tissue. Cellular vulnerability to hemoglobin is largely a function of the activity of the heme oxygenase (HO) enzymes, which consist of inducible HO-1 and constitutively-expressed HO-2. HO activity has antioxidant and anti-inflammatory effects due to heme/hemin removal and generation of two breakdown products, biliverdin (converted to bilirubin by biliverdin reductase) and carbon monoxide. Prior studies have demonstrated that HO-1 overexpression by cultured astrocytes provides robust protection against heme-mediated injury, while HO-1 knockout is deleterious. In vivo, initial results indicate that transgenic mice overexpressing HO-1 in astrocytes sustain significantly less mortality and blood-brain barrier disruption after experimental ICH than their wild-type counterparts. Furthermore, systemic treatment with HO-1 inducers increases HO-1 in perivascular astrocytes and is also protective. The broad goal of this project is to further define the therapeutic potential of astrocyte HO-1 overexpression after ICH, using specific genetic methods for proof of concept followed by randomized blinded trials of translationally-relevant pharmacotherapies. Our experimental aims are as follows: 1) Produce striatal hematomas in wild-type (WT), GFAP-Cre-HMOX1fl/fl (astrocyte HO-1 KO), and GFAP.HMOX1 mice (astrocyte HO-1 overexpression) by stereotactic injection of blood or collagenase. Compare mortality, blood-brain barrier breakdown, striatal cell loss, inflammatory response, and behavioral/cognitive outcome. 2) Quantify perihematomal blood flow, oxygen saturation, and hematoma size in WT, GFAP-Cre-Hmox1fl/fl and GFAP.HMOX1 mice after ICH using micro ultrasound combined with photoacoustic imaging. Quantify blood vessels with unbiased histological analysis guided by design-based stereology. 3) Randomize GFAP-Cre- Hmox1fl/fl mice and Hmox1fl/fl controls to treatment with HO-1 inducers (sulforaphane, hemin) or vehicle, administered i.p. beginning 3 hours after striatal blood or collagenase injection. Quantify the effect on outcome as described above. It is hoped that completion of these aims will establish the benefit of astrocyte HO-1 overexpression after spontaneous ICH, and also demonstrate the feasibility of accomplishing this end with selected pharmacotherapies. This information will then provide the rational basis for clinical trials of novel agents for a stroke subtype that currently has few therapeutic options and a grim prognosis.
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