DOI: 10.1097/01.ana.0000211006.86645.ef
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Issn Print: 0898-4921
Publication Date: 2006/07/01
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Excerpt
Oxidative stress is a disturbance in the balance of pro-oxidant and antioxidant forces that can cause tissue injury. Formation of reactive oxygen species occurs in health and is accentuated by disease. Evolution has provided endogenous antioxidant defenses including superoxide dismutase (SOD) and glutathione peroxidase, in addition to dietary low molecular weight antioxidants (LMWA) such as ascorbate and α-tocopherol. There are 3 forms of SOD, one of which is SOD1. SOD1 is abundantly expressed in brain. One would predict that elimination of this enzyme should decrease tissue tolerance to oxidative stress. On the other hand, one would predict that SOD1 overexpression should increase antioxidant defenses and tolerance to ischemia or traumatic brain injury (TBI). The current study started off examining mice overexpressing SOD1, which were subjected to TBI. In contrast to previous studies of ischemia/reperfusion, SOD1 overexpression failed to alter TBI outcome. This caused the authors to examine SOD1 knockouts. Absence of effect of SOD1 overexpression on outcome provided reason to expect that SOD1 deletion would also have no effect. This was not the case. Instead, SOD1 knockouts had slightly better neurologic outcome measured at 14 days post-TBI and this was associated with less severe reactive gliosis and decreased histologic damage when compared with normal (wild type) mice subjected to TBI. The remainder of this report explores the mechanism for this unexpected finding. Edema was examined at 24 hours post-TBI and there was no effect of the SOD1 knockout. The amount of endogenous LMWA was measured in knockouts and wild-type mice. Basal levels were higher in the knockouts indicating an adaptive response to SOD1 deficiency. However, although LMWA were rapidly depleted post-TBI in wild types due to the initial oxidative burst, LMWA concentrations were spared in the knockout mice. This suggested that downstream products of superoxide formation during the oxidative burst were decreased in the knockouts. In other words, SOD1 converts superoxide to hydrogen peroxide. Hydrogen peroxide is eliminated by glutathione peroxidase. Rapid conversion of superoxide to hydrogen peroxide could overwhelm endogenous glutathione peroxidase allowing hydrogen peroxide concentrations to increase. This could result in conversion of hydrogen peroxide to the highly reactive hydroxyl radical, or more interestingly, activate nuclear factor-κB (NF-κB). NF-κB is important because it serves as a signal between the cytosol and the nucleus causing up-regulated synthesis of a variety of gene products, some of which are protective and some of which accelerate cell death. To test this, NF-κB activation was assessed. TBI dramatically increased NF-κB activation in wild-type mice, but not in SOD1 knockouts. Hydrogen peroxide is believed to be the principal stimulus causing NF-κB activation. The authors did not measure hydrogen peroxide but speculated that reduced conversion of superoxide to hydrogen peroxide in the SOD1 knockouts decreased the stimulus for NF-κB activation. It remains controversial whether NF-κB should be inhibited to protect the brain because it stimulates synthesis of both beneficial and detrimental proteins. The authors believe their data demonstrating both improved outcome and reduced NF-κB activation in the SOD1 knockouts argue in favor of inhibited NF-κB activation as a neuroprotective strategy.
