Potential therapeutic effects of Nrf2 activators on intracranial hemorrhage

Intracranial hemorrhage (ICH) is a devastating disease which induces high mortality and poor outcomes including severe neurological dysfunctions. ICH pathology is divided into two types: primary brain injury (PBI) and secondary brain injury (SBI). Although there are numerous preclinical studies documenting neuroprotective agents in experimental ICH models, no effective drugs have been developed for clinical use due to complicated ICH pathology. Oxidative and inflammatory stresses play central roles in the onset and progression of brain injury after ICH, especially SBI. Nrf2 is a crucial transcription factor in the anti-oxidative stress defense system. Under normal conditions, Nrf2 is tightly regulated by the Keap1. Under ICH pathological conditions, such as overproduction of reactive oxygen species (ROS), Nrf2 is translocated into the nucleus where it up-regulates the expression of several anti-oxidative phase II enzymes such as heme oxygenase-1 (HO-1). Recently, many reports have suggested the therapeutic potential of Nrf2 activators (including natural or synthesized compounds) for treating neurodegenerative diseases. Moreover, several Nrf2 activators attenuate ischemic stroke-induced brain injury in several animal models. This review summarizes the efficacy of several Nrf2 activators in ICH animal models. In the future, Nrf2 activators might be approved for the treatment of ICH patients.