# Protective effect of astrocyte heme oxygenase-1 after intracerebral hemorrhage

> **NIH NIH R01** · UNIVERSITY OF MARYLAND BALTIMORE · 2020 · $337,969

## Abstract

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.

## Key facts

- **NIH application ID:** 9914357
- **Project number:** 5R01NS095205-06
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** RAYMOND F REGAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $337,969
- **Award type:** 5
- **Project period:** 2018-09-05 → 2021-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9914357

## Citation

> US National Institutes of Health, RePORTER application 9914357, Protective effect of astrocyte heme oxygenase-1 after intracerebral hemorrhage (5R01NS095205-06). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/9914357. Licensed CC0.

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