Potential therapeutic effects of Nrf2 activators on intracranial hemorrhage

Abstract

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.

Pyridoxal Isonicotinoyl Hydrazone Improves Neurological Recovery by Attenuating Ferroptosis and Inflammation in Cerebral Hemorrhagic Mice

“…ICH accounts for about 10%–15% of all strokes and has become the leading cause of death in China [ 28 ]. Inflammation, oxidative stress, neurotoxicity, and other factors accelerate secondary brain injury and eventually induce irreversible neuronal injury, which seriously affects the prognosis of ICH [ 29 , 30 ]. Excessive iron and ROS accumulation are considered major contributors to ICH-induced secondary brain injury.…”

The Role of Organosulfur Compounds as Nrf2 Activators and Their Antioxidant Effects

“…Therefore, drugs able to interfere with Nrf2–Keap1 interaction are of great interest for the treatment of such diseases. Despite the advancement in research for the discovery of Nrf2 activators, only a few approved Nrf2 activators are available [ 5 , 6 , 7 , 8 ], such as sulforaphane, oltipraz, ergothioneine, and L-carbocysteine [ 2 , 9 , 10 , 11 , 12 , 13 , 14 , 15 ].…”

HDAC6 Inhibition Rescues Oxidative Stress-derived Neuronal Apoptosis Following Intracerebral Hemorrhage Via MDH1 Acetylation

“…However, there is currently no effective treatment for ICH. Accumulating evidence suggests that oxidative stress is an important inducer of brain injury following ICH (4)(5)(6)(7). Additionally, neurons are sensitive and susceptible to oxidative stress injury and predisposed to apoptosis when oxidative stress occurs (8, 9), Therefore, targeting the oxidative stress response is an important therapeutic strategy for ICH.…”