Oxidative Stress Following Intracerebral Hemorrhage: From Molecular Mechanisms to Therapeutic Targets

Abstract

Intracerebral hemorrhage (ICH) is a highly fatal disease with mortality rate of approximately 50%. Oxidative stress (OS) is a prominent cause of brain injury in ICH. Important sources of reactive oxygen species after hemorrhage are mitochondria dysfunction, degradated products of erythrocytes, excitotoxic glutamate, activated microglia and infiltrated neutrophils. OS harms the central nervous system after ICH mainly through impacting inflammation, killing brain cells and exacerbating damage of the blood brain barrier. This review discusses the sources and the possible molecular mechanisms of OS in producing brain injury in ICH, and anti-OS strategies to ameliorate the devastation of ICH.

Keywords: anti-oxidative stress; brain injury; intracerebral hemorrhage; oxidative stress; reactive oxygen species.

Figure 1

The primary sources of ROS/RNS following ICH. Following ICH, the destruction of erythrocytes in a hematoma releases hemoglobin and heme. The RBC and degraded hemoglobin and heme are phagocyted by microglia/macrophages. Hemoglobin is then oxidized to methemoglobin to generate free radicals. Heme is metabolized by heme oxygenase into biliverdin, iron and carbonic oxide. Iron is transferred to neurons mediated by the transferrin delivery system, where iron reacts with H₂O₂ through the Fenton reaction to produce •OH, which is more toxic. The opening of inner membrane anion channels and mitochondrial permeability transition pore results in ROS release. Besides, excessive glutamate following ICH activates postsynaptic neuron NMDA receptors, promotes Ca²⁺ influx and intracellular Ca²⁺ overload, triggering the synthesis of neuronal nitric oxide and superoxide via activating neuronal nitric oxide synthase and nicotinamide adenine dinucleotide phosphate oxidases (NOXs) respectively. The polymerization of nitric oxide and superoxide forms peroxynitrite. Moreover, NOX in microglia/macrophages is activated to generate O₂· and NOS converts L-arginine to L-citrulline to produces NO. HO, heme oxygenase; Hb, hemoglobin; H₂O₂, hydrogen peroxide; •OH, hydroxyl radical; ICH, intracerebral hemorrhage; IMAC, inner membrane anion channel; mPTP, mitochondrial permeability transition pore; NOXs, nicotinamide adenine dinucleotide phosphate oxidases; NO, nitric oxide; NOS, nitric oxide synthase; ONOO, peroxynitrite; RBC, red blood cell; ROS/RNS, reactive oxygen/nitrogen species; O₂·, superoxide anion radical; Tf, transferrin.

Figure 2

The main destructive effect of OS to brain following ICH. The production of ROS/RNS significantly exceeds the body’s antioxidant capacity after ICH, resulting in irreversible damage to lipids, proteins, and DNA, ultimately inducing multiple forms of cell death pathways (apoptosis, necrosis, necroptosis, ferroptosis and autophagy) via activating related molecular networks or genes. Besides, OS increases the level of NF-κB, which upregulates proinflammatory cytokines, inflammatory molecules and MMPs to result in inflammation. MMPs increase the permeability of capillaries by degrading the basement membrane and tight junction structure of cerebrovascular endothelial cells, thereby contributing to inflammation and BBB disruption. Moreover, OS can directly injure endothelial cells and damage the BBB. BBB, blood brain barrier; MMPs, matrix metalloproteinases; mPTP, mitochondrial permeability transition pore; NF-κB, nuclear factor-kappa B; SBI, secondary brain injury.