Chemical Basis of Reactive Oxygen Species Reactivity and Involvement in Neurodegenerative Diseases

Abstract

Increasing numbers of individuals suffer from neurodegenerative diseases, which are characterized by progressive loss of neurons. Oxidative stress, in particular, the overproduction of Reactive Oxygen Species (ROS), play an important role in the development of these diseases, as evidenced by the detection of products of lipid, protein and DNA oxidation in vivo. Even if they participate in cell signaling and metabolism regulation, ROS are also formidable weapons against most of the biological materials because of their intrinsic nature. By nature too, neurons are particularly sensitive to oxidation because of their high polyunsaturated fatty acid content, weak antioxidant defense and high oxygen consumption. Thus, the overproduction of ROS in neurons appears as particularly deleterious and the mechanisms involved in oxidative degradation of biomolecules are numerous and complexes. This review highlights the production and regulation of ROS, their chemical properties, both from kinetic and thermodynamic points of view, the links between them, and their implication in neurodegenerative diseases.

Keywords: NADPH oxidase; hydrogen peroxide; hydroperoxides; hydroxyl radical; neurodegenerative diseases; reactive oxygen species; superoxide anion; superoxide dismutase.

Figure 1

The chemical basis of Reactive Oxygen Species (ROS) generation—primary radical and molecular species are produced by incomplete reduction of molecular oxygen and can further react with an organic substrate to generate substrate-derived ROS. Metal ions are engaged in electron transfer (through metalloenzymes in vivo), but also involved in both Fenton and Haber-Weiss reactions, and in the reduction of hydroperoxide into alkoxyl radical.

Figure 2

The chemical reactions of the superoxide and the perhydroxyl radicals.

Figure 3

The chemical reactions of the hydroxyl radical.

Figure 4

The chemical reactions of hydrogen peroxide, peroxyl and alkoxyl radicals.

Figure 5

The direct involvement of ROS in lipid peroxidation and protein carbonylation. (A) the mechanism of 4-HNE formation from ROS-induced polyunsaturated omega-6 fatty acid peroxidation (from Pryor and Porter [125]); 4-HNE is able to form adducts with lipoic acid, proteins (C, H and K residues) and DNA bases; (B) ROS-induced protein carbonylation and cleavage (from Stadtman and Levine [43]).