Figure 1: Presumed Mechanism of H

Ischemic insults create tissue hypoxia, stimulating a complex cascade (not shown) that results in the release of superoxide (O2−•). When O2−• is present in excess (i.e., when compensatory mechanisms become saturated), it directly causes the reduction of transition metal ions, including Fe3+ and Cu2+, which in turn, generates hydroxyl radicals (•OH) by the Fenton reaction. The •OH is the strongest of the oxidant species and is the direct effector of DNA injury and lipid membrane peroxidation, which releases HNE and MDA, causing direct cellular injury and stimulating apoptosis. Unlike O2−• and H2O2, there is no known detoxification system for •OH; therefore, scavenging •OH is a critical antioxidant process. Molecular hydrogen (H2), which freely permeates the cell wall and diffuses into the cytosol and mitochondria, reduces the hydroxyl radical to water and thus mitigates •OH-mediated tissue injury. HNE = 4-hydroxyl-2-nonenal; MDA = malondialdehyde; SOD = superoxide dismutase.