V

■ Hemoglobin Ferritin

Figure 4 Biochemistry of oxygen radical formation via the peroxynitrite pathway and the dismutation/Fenton reaction pathway. O2-', superoxide radical; NO', nitric oxide or nitrogen monoxide; ONOO-, peroxynitrite anion; ONOOH, peroxynitrous acid; 'NO2, nitrogen dioxide; 'OH, hydroxyl radical; ONOOCO2, nitrosoperoxocarbonate; 'CO3, carbonate radical; SOD, superoxide dismutase; H2O2, hydrogen peroxide; GSH PX, glutathione peroxidase.

H2O2

hemolytic decomposition to form the highly reactive nitrogen dioxide radical ('NO2) and hydroxyl radical ('OH). Probably more important physiologically, peroxynitrite will react with carbon dioxide (CO2) to form nitrosoperoxocarbonate (ONOOCO2), which decomposes into 'NO2 and carbonate radical ('CO3). Figure 4 summarizes the biochemistry of peroxynitrite generation as well as the fact that dismutation of superoxide radical to hydrogen peroxide via superoxide dismutase (SOD) can also lead to the formation of 'OH via the iron-catalyzed Fenton reaction. This latter process undoubtedly plays a role along with peroxynitrite in posttraumatic and postischemic oxidative damage.

Each of the peroxynitrite-derived radicals ("OH, "NO2, and "CO3) can initiate lipid peroxidative damage (LP) cellular damage by abstraction of an electron from a hydrogen atom bound to an allylic carbon in polyunsaturated fatty acids, or cause protein carbonylation by reaction with susceptible amino acids (e.g., lysine, cysteine, or arginine). Moreover, the aldehydic LP products malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE) can bind to cellular proteins, compromising their structural and functional integrity. 4-HNE is the more interesting of the two aldehydes in that it is itself neurotoxic. 47 In addition, "NO2 can nitrate the 3 position of tyrosine residues in proteins; 3-NT is a specific footprint of peroxynitrite-induced cellular damage. Increased 3-NT has been found in injured CNS tissue in models of stroke,48 TBI,49 and SCI,50 which is indicative of a role of peroxynitrite in each of these acute insults.

Compared with other short-lived ROS (e.g., H2O2) and free-radical species (e.g., superoxide and "OH), peroxynitrite possesses a much longer half-life (approximately 1 s), which enables it to diffuse across intracellular and cellular membranes. In addition, the relatively long lifespan of peroxynitrite makes it a more tractable target for successful scavenging. Indeed, several new compound entities have been identified as having the ability to react directly with peroxynitrite, decomposing it into nonreactive products. The chemical structures of several new compound entities that scavenge peroxynitrite, many of which have been shown to have neuroprotective properties in CNS injury animal models, are shown in Figure 5 and include uric acid, dimethylthiourea (DMTU), the indoleamine melatonin,53 the pyrrolpyrimidine antioxidant U-101033E,54 and penicillamine.55 Perhaps the best characterized with regard to chemical scavenging is penicillamine, which is a stoichiometric scavenger with one molecule of penicillamine decomposing one molecule of peroxynitrite; but penicillamine is also destroyed in the process (see the scavenging mechanism in Figure 5). Although such an inefficient scavenging mechanism may be adequate to produce neuroprotective effects, a catalytic scavenging mechanism wherein one molecule of the antioxidant can decompose many molecules of the oxidant without being destroyed would represent a more desirable peroxynitrite scavenging pharmacophore, but one that remains to be identified. Recent studies have demonstrated that the nitroxide new compound entity tempol can catalytically scavenge the peroxynitrite-derived radical species NO2 and CO3 (Figure 6).56 Tempol has beneficial effects in rodent TBI, SCI, and stroke models that may be a manifestation of its ability to efficiently scavenge highly reactive peroxynitrite-derived radicals. Other nitroxides may share this property, although the structure-activity relationship for this potent and efficient radical scavenging property remains to be established.

Perhaps an even better antioxidant approach would be to combine two mechanistically additive or complementary antioxidant pharmacophores into a single new compound entity, such as a dual LP inhibitor or a LP inhibitor coupled

Uric acid

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