Progress in Research on Regulated Cell Death in Cerebral Ischaemic Injury After Cardiac Arrest

Abstract

Ischaemic damage to the brain is the main cause of brain injury after cardiac arrest. The current treatment focuses on early reperfusion, but reperfusion tends to cause reperfusion injury, which is a significant problem. Cell death is an irreversible and normal end to cell life, playing key roles in maintaining the homeostasis and development of multicellular organisms. To date, cell death can be classified into two categories: accidental cell death (ACD) and regulated cell death (RCD). Cell death plays an indispensable role in cerebral ischaemia injury. An increasing number of scholars are exploring the mechanisms and sites of cell death during targeted inhibition of cerebral ischaemia to treat cerebral ischaemia injury. In addition to the established cell death pathways, namely, the apoptosis, pyroptosis and necroptosis pathways, ferroptosis and cuproptosis pathways have been discovered. This article reviews the cell death pathways involved in ischaemic brain injury, discusses the roles played by these death modalities, and suggests therapeutic directions for future targeting of cell death sites.

Keywords: cerebral ischaemic injury; cuproptosis; mechanism; regulated cell death; therapy.

FIGURE 1

Following cerebral ischemia and hypoxia, brain activity is compromised, triggering a rapid onset of the ischemic cascade. The depletion of adenosine triphosphate (ATP) and glucose results in the dysfunction of the Na⁺/K⁺ ATPase pump, subsequently leading to mitochondrial injury and intracellular calcium overload. This cascade of events significantly exacerbates immediate cell necrosis or apoptosis.

FIGURE 2

Apoptosis promotes cerebral ischaemic injury via Caspase3, Caspase6, Caspase7, Caspase8, Caspase10 and BCL2. Pyroptosis promotes cerebral ischaemic injury through GSDMD, Caspase1 and Caspase11. Necroptosis promotes cerebral ischaemic injury through RIPK3 and MLKL. Ferroptosis promotes cerebral ischaemic injury through ROX and GPX4. Cuproptosis promotes and inhibits cerebral ischaemic injury through FDX1.

FIGURE 3

VAD‐FMK and Ac‐DEVD‐CHO protect against cerebral ischaemic injury by inhibiting caspase, thereby inhibiting apoptosis. Ac‐YVAD‐cmk inhibits cerebral ischaemic injury by inhibiting caspase1 activity, Ac‐FLTD‐CMK inhibits GSDMD activity, and wedelolactone inhibits pyroptosis by inhibiting caspase11. GSK872 affects necroptosis by inhibiting RIPK3 and necrosulfonamide by inhibiting MLKL function; therefore, they may confer protection against cerebral ischaemic injury. Deferoxamine inhibits Fe ion production, liproxstatin‐1 inhibits ROS production, and selenium inhibits GPX4 activity, all of which inhibit ferroptosis and thus protect against ischaemic brain injury. UK5099 inhibits MPC, and rotenone and antimycin inhibit the ETC, suppressing cuproptosis and thus preventing cerebral ischaemic injury.

FIGURE 4

The central mechanism of regulatory cell death. Apoptosis is classified into extrinsic and intrinsic apoptosis. Extrinsic apoptosis is caused by the binding or dissociation of death receptor ligands and their receptor ligands. DNA damage, hypoxia, metabolic stress and other factors can induce extrinsic apoptosis. Caspase1 and Caspase11 lead to GSDMD cleavage, and the cleavage products bind to phospholipids, resulting in membrane cleavage. A ligand binds to a death‐inducing complex to form necrosomes, which undergo conformational changes resulting in membrane rupture. Ligand–death receptor binding also promotes the ROS production system by increasing iron levels and inhibits the antioxidant system causing lipid peroxidation, leading to ferroptosis. The accumulation of intracellular copper ions, which directly bind to acylated lipid components in the TCA cycle, blocks the TCA cycle, triggers proteotoxic stress, and induces cell death.