Endogenous Antioxidants

Superoxide Dismutase

The brain has several defensive mechanisms with which to protect itself from oxidative stress. SOD neutralizes superoxide to H2O2 (29). Three isoenzymes of SOD are characterized by their subcellular localization and prosthetic metal ions. Cu/Zn-SOD (or SOD1) mainly localizes in cytosol, whereas Mn-SOD (or SOD2) is distributed predominantly in the mitochondria. Extracellular SOD (EC-SOD or SOD3) is found in the extracellular space. The role of SOD1 in focal cerebral ischemia was delineated in studies that used both transgenic SOD1-overexpressing and SOD1-deficient mice. Consistent with a beneficial role, SOD1-transgenic mice exposed to temporary MCAO had smaller infarct sizes than wildtype mice (40). Similarly, SOD1-deficient mice suffered increased neuronal cell death and brain edema after MCAO (41). Similar observations were made in SOD2-knockout mice, which had exacerbated injury (42). EC-SOD is presumed to protect against superoxide produced by membrane-bound NADPH oxidase in inflammatory cells (43). EC-SOD overexpression provides neuroprotection in mice following focal cerebral ischemia (44), whereas EC-SOD-deficient mice have a worsened outcome from experimental stroke (45). Interestingly, SOD does not always protect the brain from ischemia. Neonatal SOD1-transgenic animals had increased injury following hypoxia-ischemia, and this was associated with higher levels of H2O2, possibly due to lower levels of downstream antioxi-dants glutathione peroxidase (GPx) and catalase (46).

Catalase and Glutathione Peroxidase

Whereas SOD dismutates superoxide to H2O2 and oxygen O2, H2O2 is another oxidant that can freely cross cell membranes. H2O2 is both a product of and a source of free radical reactions. Endogenous H2O2 might be converted, either by catalase or GPx, to H2O, or it might generate the highly reactive free hydroxyl radical (OH •) via the Fenton reaction (47). H2O2 is then scavenged by GPx at the expense of reduced glutathione (GSH) to produce H2O and oxidized glutathione (GSSG). Catalase and GPx are present in the brain (47), with GPx present in the cytosol and catalase localized mainly in peroxisomes (48). Two GPx mimics, ebselen and edaravone, have been shown to be able to reduce infarct volume in experimental focal ischemia (49,50), and viral vector-mediated overexpression of catalase and GPx are associated with improved neuronal survival after experimental stroke (51,52 ).

Low-Molecular-Weight Reductants

Glutathione, ascorbate, and alpha-tocopherol can reduce H2O2 to water and scavenge free radicals; they react preferentially with the chain-propagating radicals to yield a stable radical product of the antioxidants. By donating electrons to free radicals, chain-breaking antioxidants spare other molecules from oxidation. This mechanism is also important in protecting the brain from focal ischemia.

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