Mechanisms of Oxidative Stress and Therapeutic Targets following Intracerebral Hemorrhage

Abstract

Oxidative stress (OS) is induced by the accumulation of reactive oxygen species (ROS) following intracerebral hemorrhage (ICH) and plays an important role in secondary brain injury caused by the inflammatory response, apoptosis, autophagy, and blood-brain barrier (BBB) disruption. This review summarizes the current state of knowledge regarding the pathogenic mechanisms of brain injury after ICH, markers for detecting OS, and therapeutic strategies that target OS to mitigate brain injury.

Figure 1

The production of reactive oxygen species after cerebral hemorrhage: hemin and divalent iron ions enter the cell through the corresponding receptors on the cell membrane, and further, Fenton reaction occurs in the mitochondria, thereby generating excess ROS; glutamate and thrombin activate ion channel receptors on the cell membrane to promote Ca²⁺ influx; in addition, the VDAC and IP(3)R located in the mitochondria and the endoplasmic reticulum are connected through GRP75, so that the Ca²⁺ in the endoplasmic reticulum flows into the mitochondria, and the Ca²⁺ in the mitochondria is further overloaded, and the MPTPA channel on the mitochondria is opened and released. The H₂O₂ produced at the two sites of site IQ and site IIIQo in the mitochondria generates ROS when it encounters Fe(III). Endoplasmic reticulum UPR can reduce ERS. When ERS cannot be relieved, certain UPR components (such as C/EBP homologous protein CHOP) may cause oxidative stress; in addition, in the stressed ER, the imbalance of disulfide bond formation and breaking may lead to the accumulation of reactive oxygen species (ROS) and cause oxidative stress. ROS: reactive oxygen species; Fe²⁺: ferrous iron; AMPA: α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor; NMDA: N-methyl-D-aspartic acid receptor; HO-1: heme oxygenase-1; DMT: divalent metal transporter 1; MPTP: mitochondrial permeability transition pore; VDAC: voltage-dependent anion channel; ER: endoplasmic reticulum; IP3R: inositol 1,4,5-trisphosphate receptor; ERO1: ER oxidase 1; CHOP: C/EBP homologous protein; UPR: unfolded protein response; PDI: protein disulfide isomerases; LRP1: lipoprotein receptor-related protein; NOX4: adenine dinucleotide phosphate oxidase 4.

Figure 2

Summary of mechanisms by which OS aggravates SBI after ICH: after ICH, activated phagocytes, mitochondria, ER, and RBC lysates all cause excess release of ROS. This increase in OS exacerbates the inflammatory response, apoptosis, autophagy, and BBB disruption, with further SBI aggravation. BBB: blood-brain barrier; ICH: intracerebral hemorrhage; OS: oxidative stress; ROS: reactive oxygen species; SBI: secondary brain injury.

Figure 3

Description of antioxidant enzyme system regulation via the Keap1-Nrf2-ARE pathway. (a) Under normal basal conditions, Keap1 binds Nrf2 and keeps its level low by ubiquitination and proteasomal degradation; (b) under OS conditions, Keap1 is oxidized by OS, and dissociation of Nrf2 from Keap1 enables Nrf2 to translocate to the nucleus. Nrf2 combines with the small Maf protein to form a Nrf2-Maf heterodimer, and Nrf2 binds to accessory protein and then ARE activates gene expression of HO-1, NQO1, GPX, SOD, CAT, and the autophagy protein p62. ARE: antioxidant response element; CAT: catalase; Cul3: Cullin3; GPX: glutathione peroxidase; HO-1: heme oxygenase-1; ICH: intracerebral hemorrhage; Keap1: Kelch-like ECH-associated protein 1; Maf: musculoaponeurotic fibrosarcoma; NQO1: NAPDH quinone oxidoreductase 1; Nrf2: nuclear factor erythroid 2-related factor 2; OS: oxidative stress; SOD: superoxide dismutase.