Oxidative Stress in Intracerebral Hemorrhage: Sources, Mechanisms, and Therapeutic Targets

Abstract

Intracerebral hemorrhage (ICH) is associated with the highest mortality and morbidity despite only constituting approximately 10-15% of all strokes. Complex underlying mechanisms consisting of cytotoxic, excitotoxic, and inflammatory effects of intraparenchymal blood are responsible for its highly damaging effects. Oxidative stress (OS) also plays an important role in brain injury after ICH but attracts less attention than other factors. Increasing evidence has demonstrated that the metabolite axis of hemoglobin-heme-iron is the key contributor to oxidative brain damage after ICH, although other factors, such as neuroinflammation and prooxidases, are involved. This review will discuss the sources, possible molecular mechanisms, and potential therapeutic targets of OS in ICH.

Figure 1

The OS-induced death pathway mediated by MMP-9. Hb released into extracellular space via complement-mediated cell lysis after ICH is a potent oxidant which can produce a plenty of free radicals such as superoxide (O₂ ^∙−), NO, and their conjunctive metabolite, peroxynitrite (ONOO⁻). These ROS/RNS activate MMP-9 possibly through NF-κB activation and finally lead to neuronal death. ICH: intracerebral hemorrhage; MMP-9: matrix metalloproteinases-9.

Figure 2

The sources of oxidative stress and the cell death pathways induced by oxidative stress following intracerebral hemorrhage. Oxidative stress after ICH is a consequence of prooxidant overproduction as well as deactivation of antioxidases such as SOD. The Hb-heme-iron metabolic axis due to erythrocyte lysis represents the major sources of ROS. Neuroinflammation evoked by ICH involves the activation of microglia and the infiltration of leukocyte which is another important contributor to the production of ROS. Activation of prooxidases including NOS and NOX during ICH also releases plenty of free radicals. Other factors which can generate ROS include mitochondria dysfunction. Oxidative stress causes cell death by direct oxidation of lipid, protein, and DNA or via induction of neuronal death mediated by PKC/CK2, ERK, NF-κB, JNK signaling pathways as well as cytochrome c release, and MMP-9 activation. PKC: protein kinase C; ERK: extracellular signal-regulated kinase; NF-κB: nuclear factor kappa B; JNK: c-Jun N-terminal kinase; ROS: reactive oxygen species; RNS: reactive nitrogen species; NOS: nitric oxide synthase; NOX: nicotinamide adenine dinucleotide phosphate oxidase; MMP-9: matrix metalloproteinases-9.