Ferroptosis, a Regulated Neuronal Cell Death Type After Intracerebral Hemorrhage

Abstract

Ferroptosis is a term that describes one form of regulated non-apoptotic cell death. It is triggered by the iron-dependent accumulation of lipid peroxides. Emerging evidence suggests a link between ferroptosis and the pathophysiological processes of neurological disorders, including stroke, degenerative diseases, neurotrauma, and cancer. Hemorrhagic stroke, also known as intracerebral hemorrhage (ICH), belongs to a devastating illness for its high level in morbidity and mortality. Currently, there are few established treatments and limited knowledge about the mechanisms of post-ICH neuronal death. The secondary brain damage after ICH is mainly attributed to oxidative stress and hemoglobin lysate, including iron, which leads to irreversible damage to neurons. Therefore, ferroptosis is becoming a common trend in research of neuronal death after ICH. Accumulative data suggest that the inhibition of ferroptosis may effectively prevent neuronal ferroptosis, thereby reducing secondary brain damage after ICH in animal models. Ferroptosis has a close relationship with oxidative damage and iron metabolism. This review reveals the pathological pathways and regulation mechanism of ferroptosis following ICH and then offers potential intervention strategies to mitigate neuron death and dysfunction after ICH.

20-HETE Participates in Intracerebral Hemorrhage-Induced Acute Injury by Promoting Cell Ferroptosis

“…Emerging data suggest that ferroptosis contributes to ICH-induced secondary brain injury and might be one of most influential cell death types after ICH (4,5,16). Therefore, therapy that targets the inhibition of ferroptosis may effectively prevent neuronal death, thereby reducing secondary brain injury after ICH (17). 20-Hydroxy-5,8,11,14-eicosatetraenoic acid (20-HETE) plays an important role in regulating a wide variety of normal physiological functions as well as the pathogenesis of diverse disease conditions (18).…”

“…Emerging data suggest that ferroptosis contributes to ICH-induced secondary brain injury and might be one of most influential cell death types after ICH ( 4 , 5 , 16 ). Therefore, therapy that targets the inhibition of ferroptosis may effectively prevent neuronal death, thereby reducing secondary brain injury after ICH ( 17 ).…”

Scalp Acupuncture Protects Against Neuronal Ferroptosis by Activating The p62-Keap1-Nrf2 Pathway in Rat Models of Intracranial Haemorrhage

“…Evidence is amassing which connects the pathways underlying ferroptosis to neurological pathologies such as Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis (Zille et al 2019;Devos et al 2019;Masaldan et al 2019;De Gregorio-Rocasolano et al 2019). Furthermore, data from experiments have implied that ferroptosis also arises in haemorrhagic cerebrovascular accidents (Bai et al 2020;Li et al 2017a, b, c;Zhang et al 2018a, b;Guo et al 2020). It was demonstrated that surplus quantities of iron were released following the degradation of haemoglobin after the development of an intracerebral haematoma.…”

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

“…It is reported that large amounts of ferrous ions are transported to neurons by transferrin, which triggers a Fenton reaction and produces a large number of ROS, resulting in neuronal cell death. Currently, methods to monitor ferroptosis rely mainly on measuring ROS production, lipid peroxidation, iron accumulation, and abilities of ferroptosis inhibitors to block cell death [34][35][36]. According to the previous research results, the ferroptosis inhibitors, ferrostatin-1 and liproxstatin-1, have shown their therapeutic value in animal models of ICH; however, their "ROS inhibitor" roles hinted that they may inhibit other pathways of cell death at the same time [37][38][39].…”