Oxidant Systems in the Brain

Many prooxidant and antioxidant enzymes are known to participate in oxidative stress-induced signaling and injury in cerebral ischemia. Prooxidants can be divided into 3 major classes: ()) NOS, which generate NO; () i) cyclooxygenases (COXs), xanthine dehydrogenase, xanthine oxidase, and NADPH oxidase, which produce superoxide anion; and (iii) myeloper-oxidase (MPO) and monoamine oxidase, which generate hypochlorous acid and hydrogen peroxide (H2O2), existent in peripheral neutrophils and various brain cells ( 29). Antioxidants in the brain include the superoxide dismutases (SODs), glutathione peroxidase, and catalase, as well as the low-molecular-weight reductants glutathione, ascorbate (reduced vitamin C), and alpha-tocopherol (reduced vitamin E).

Nitric Oxide Synthase and Nitric Oxide

Three isoforms of NOS generate NO from L-arginine: the neuronal isoform (nNOS) found in neurons, the endothelial isoform (eNOS) found in vessels, and the inducible isoform (iNOS)

Figure 3 Ischemia-induced oxidative stress. Ischemia, especially followed by reperfusion, leads to increases in reactive oxygen and nitrogen species through a variety of mechanisms. Direct mitochondrial stress can lead to impaired respiratory function and accumulation of ROS. Other sources of ROS include superoxide (O2-) generation from inflammatory cell activation of NADPH oxidase and induction of COX-2. Calcium activates xanthine oxidase, whereas NOS converts L-arginine to NO. Superoxide disutase converts O2- to hydrogen peroxide (H2O2), an oxidant that can react with Fe2+ to generate hydroxyl radical (-OH). H2O2 can be detoxified through glutathione (GSH) in the presence of GPx to form GSSG and H2O. NO can also react with O2- to yield an even more toxic oxidant peroxynitrite (ONOO-). ONOO- then might further yield 2 other oxidants, NO2 and -OH. All oxidants can then lead to cause oxidation of macromolecules, such as lipids, proteins, and DNA, and cause direct damage to mitochondria. Furthermore, oxidants can lead to BBB damage, causing vasogenic edema and cerebral hemorrhage. Abbreviations: COX-2; cyclooxygenase-2; NOS, nitric oxide synthase; NO, nitric oxide; GPx, glutathione peroxidase; GSSG, glutathione disulfide; NO2; nitric dioxide; BBB, blood-brain barrier.

Figure 3 Ischemia-induced oxidative stress. Ischemia, especially followed by reperfusion, leads to increases in reactive oxygen and nitrogen species through a variety of mechanisms. Direct mitochondrial stress can lead to impaired respiratory function and accumulation of ROS. Other sources of ROS include superoxide (O2-) generation from inflammatory cell activation of NADPH oxidase and induction of COX-2. Calcium activates xanthine oxidase, whereas NOS converts L-arginine to NO. Superoxide disutase converts O2- to hydrogen peroxide (H2O2), an oxidant that can react with Fe2+ to generate hydroxyl radical (-OH). H2O2 can be detoxified through glutathione (GSH) in the presence of GPx to form GSSG and H2O. NO can also react with O2- to yield an even more toxic oxidant peroxynitrite (ONOO-). ONOO- then might further yield 2 other oxidants, NO2 and -OH. All oxidants can then lead to cause oxidation of macromolecules, such as lipids, proteins, and DNA, and cause direct damage to mitochondria. Furthermore, oxidants can lead to BBB damage, causing vasogenic edema and cerebral hemorrhage. Abbreviations: COX-2; cyclooxygenase-2; NOS, nitric oxide synthase; NO, nitric oxide; GPx, glutathione peroxidase; GSSG, glutathione disulfide; NO2; nitric dioxide; BBB, blood-brain barrier.

found in inflammatory cells. In addition to macrophages and microglia, iNOS, under pathologic conditions, can be expressed in other cells, including neurons, astrocytes, and endothelial cells (30). Depending on the isoform and cell type in which NO is produced, NOS plays various roles in ischemic injury (31). nNOS (or NOSl), upregulated in neurons via NMDA receptor-stimulation, mediates early injury, whereas iNOS (or NOS2) is thought to contribute to late injury due to its production in inflammatory cells. eNOS (or NOS3), though expressed at low levels compared to the other isoforms, acts as a vasodilator and is believed to be protective by enhancing CBF. NO can further mediate cell damage by reacting with superoxide anion to form peroxynitrite (ONOO-), which is especially damaging to DNA.

Superoxide-Generating Systems

Superoxide anion is a major oxidant generated in the brain parenchyma after middle cerebral artery occlusion (MCAO) (29). COX-1, COX-2, xanthine dehydrogenase, xanthine oxidase, and NADPH oxidase are all involved in superoxide generation. COX-1 is constitutively expressed, whereas COX-2 is inducible. During prostanoid synthesis, COX-2 generates superoxide ion (32 ). COX-2 upregulation has been detected following experimental cerebral ischemia (33,34), and COX-2 knockout mice exhibit reduced susceptibility to ischemic brain injury and NMDA-mediated neurotoxicity (35). Furthermore, animals treated with NS-398, an inhibitor of COX-2, also had reduced infarct sizes (36). In contrast, COX-1 might have a beneficial role in ischemia, as COX-l-deficient mice have increased susceptibility, possibly due to downstream effects of prostaglandins on augmenting CBF (37) . Superoxide can be generated through xanthine oxidase, which in turn, is generated from xanthine dehydrogenase via a calcium-activated protease. Superoxide is also generated in inflammatory cells, such as peripheral leukocytes and microglia, via NADPH oxidase as a defense mechanism against microbes. NADPH oxidase is a multicomponent enzyme that consists of 2 membrane-bound subunits (gp91 and p22) and 3 cytosolic subunits (p67, p47, and p40), plus Rac, a small GTPase (38). With appropriate stimuli, the cytosolic subunits translocate to the membrane, where they interact with the membrane-bound subunits to transfer electrons from NADPH to oxygen to form superoxide. NADPH oxidase appears to play a role in mediating ischemic injury, as mice lacking the gp91 subunit have smaller infarcts compared to wildtype (39 ).

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