Free radical-mediated molecular damage. Mechanisms for the protective actions of melatonin in the central nervous system.

This review briefly summarizes the multiple actions by which melatonin reduces the damaging effects of free radicals and reactive oxygen and nitrogen species. It is well documented that melatonin protects macromolecules from oxidative damage in all subcellular compartments. This is consistent with the protection by melatonin of lipids and proteins, as well as both nuclear and mitochondrial DNA. Melatonin achieves this widespread protection by means of its ubiquitous actions as a direct free radical scavenger and an indirect antioxidant. Thus, melatonin directly scavenges a variety of free radicals and reactive species including the hydroxyl radical, hydrogen peroxide, singlet oxygen, nitric oxide, peroxynitrite anion, and peroxynitrous acid. Furthermore, melatonin stimulates a number of antioxidative enzymes including superoxide dismutase, glutathione peroxidase, glutathione reductase, and catalase. Additionally, melatonin experimentally enhances intracellular glutathione (another important antioxidant) levels by stimulating the rate-limiting enzyme in its synthesis, gamma-glutamylcysteine synthase. Melatonin also inhibits the proxidative enzymes nitric oxide synthase and lipoxygenase. Finally, there is evidence that melatonin stabilizes cellular membranes, thereby probably helping them resist oxidative damage. Most recently, melatonin has been shown to increase the efficiency of the electron transport chain and, as a consequence, to reduce election leakage and the generation of free radicals. These multiple actions make melatonin a potentially useful agent in the treatment of neurological disorders that have oxidative damage as part of their etiological basis.