Oxidative stress in ischemic brain damage: mechanisms of cell death and potential molecular targets for neuroprotection

Abstract

Significant amounts of oxygen free radicals (oxidants) are generated during cerebral ischemia/reperfusion, and oxidative stress plays an important role in brain damage after stroke. In addition to oxidizing macromolecules, leading to cell injury, oxidants are also involved in cell death/survival signal pathways and cause mitochondrial dysfunction. Experimental data from laboratory animals that either overexpress (transgenic) or are deficient in (knock-out) antioxidant proteins, mainly superoxide dismutase, have provided strong evidence of the role of oxidative stress in ischemic brain damage. In addition to mitochondria, recent reports demonstrate that NADPH oxidase (NOX), an important pro-oxidant enzyme, is also involved in the generation of oxidants in the brain after stroke. Inhibition of NOX is neuroprotective against cerebral ischemia. We propose that superoxide dismutase and NOX activity in the brain is a major determinant for ischemic damage/repair and that these major anti- and pro-oxidant enzymes are potential endogenous molecular targets for stroke therapy.

FIG. 1

Main resources and pathways for oxidant generation in vivo. NO and O₂^·− are produced in the brain during ischemia/reperfusion. NO induces protein nitrosylation as well as ONOO⁻ generation by reacting with O₂^·−. SOD detoxifies O₂^·− to H₂O₂, which is converted to H₂O by catalase or GSHPx. ·OH, which is produced from H₂O₂ through the Fenton or Haber-Weiss reactions, causes cell injury through oxidized lipid, protein, DNA, and RNA. GSHPx, glutathione peroxidase; H₂O₂, hydrogen peroxide; NO, nitric oxide; O₂^·−, superoxide anion; ·OH, hydroxyl radical; ONOO⁻, peroxynitrite; SOD, superoxide dismutase. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article at www.liebertonline.com/ars).

FIG. 2.

SOD and cell death/survival pathways. Three oxidative stress-mediated pathways are shown. Oxidants cause cell death by direct oxidation of macromolecules. Oxidants can also induce redox-sensitive pathway activation, including Akt, p38, and NF-κB pathways. SOD promotes cell survival through reduction of oxidative stress and inhibition of cell death pathways. MAPK, mitogen-activated protein kinase; NF-κB, nuclear factor kappa B; PKC, protein kinase C.

FIG. 3.

Overview of NOX activation. p47^phox phosphorylation subsequently causes the cytosolic subunits p47^phox, p67^phox, and p40^phox to translocate into membranes and fuse with the catalytic subunit gp91^phox. This is followed by interaction between Rac and gp91^phox. NOX activation and subsequent oxidant generation contribute to postischemic neuronal injury, the inflammatory process, and BBB disruption. P, phosphorylation; BBB, blood–brain barrier; NOX, NADPH oxidase. (In part, from Chan PH. Reperfusion and neurovascular dysfunction in stroke: from basic mechanisms to potential strategies for neuroprotection. The Thomas Willis Lecture. International Stroke Conference 2008; New Orleans, February 20–22, 2008.) (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article at www.liebertonline.com/ars).

FIG. 4.

NOX activation in excitotoxicity after ischemia. During excitotoxicity, Ca²⁺ influx through the NMDAR causes PKCζ activation and subsequent p47^phox phosphorylation, which then initiates NOX activation, and finally contributes to cell damage through oxidant generation. NMDAR, N-methyl-d-aspartate receptor.

FIG. 5.

SOD and mitochondrial-mediated apoptosis. Cytochrome c plays a central role in apoptosis. p53 facilitates apoptosis through transcription-dependent and transcription-independent pathways. SOD inhibits both the cytochrome c–mediated and p53-mediated apoptosis pathways. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article at www.liebertonline.com/ars).