Targeting the Nrf2-Heme Oxygenase-1 Axis after Intracerebral Hemorrhage

Title:Targeting the Nrf2-Heme Oxygenase-1 Axis after Intracerebral Hemorrhage

Volume: 23 Issue: 15

Author(s): Jing Chen-Roetling and Raymond F. Regan*

Affiliation:

• Department of Emergency Medicine, Thomas Jefferson University, 1025 Walnut Street, College Building Room 813, Philadelphia, PA 19107,United States

Keywords: Astrocyte, heme, heme oxygenase, intracerebral hemorrhage, Nrf2, Stroke.

Abstract: Background: Injury to cells adjacent to an intracerebral hemorrhage (ICH) is likely mediated at least in part by toxins released from the hematoma that initiate complex and interacting injury cascades. Pharmacotherapies targeting a single toxin or pathway, even if consistently effective in controlled experimental models, have a high likelihood of failure in a variable clinical setting. Nuclear factor erythroid-2 related factor 2 (Nrf2) regulates the expression of heme oxygenase-1 (HO-1) and multiple other proteins with antioxidant and antiinflammatory effects, and may be a target of interest after ICH.

Methods: Studies that tested the effect of HO and Nrf2 in models relevant to ICH are summarized, with an effort to reconcile conflicting data by consideration of methodological limitations.

Results: In vitro studies demonstrated that Nrf2 activators rapidly increased HO-1 expression in astrocytes, and reduced their vulnerability to hemoglobin or hemin. Modulating HO-1 expression via genetic approaches yielded similar results. Systemic treatment with small molecule Nrf2 activators increased HO-1 expression in perivascular cells, particularly astrocytes. When tested in mouse or rat ICH models, Nrf2 activators were consistently protective, improving barrier function and attenuating edema, inflammation, neuronal loss and neurological deficits. These effects were mimicked by selective astrocyte HO-1 overexpression in transgenic mice.

Conclusion: Systemic treatment with Nrf2 activators after ICH is protective in rodents. Two compounds, dimethyl fumarate and hemin, are currently approved for treatment of multiple sclerosis and acute porphyria, respectively, and have acceptable safety profiles over years of clinical use. Further development of these drugs as ICH therapeutics seems warranted.

Cite this article as:

Chen-Roetling Jing and Regan F. Raymond*, Targeting the Nrf2-Heme Oxygenase-1 Axis after Intracerebral Hemorrhage, Current Pharmaceutical Design 2017; 23 (15) . https://dx.doi.org/10.2174/1381612822666161027150616

DOI https://dx.doi.org/10.2174/1381612822666161027150616	Print ISSN 1381-6128
Publisher Name Bentham Science Publisher	Online ISSN 1873-4286