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.