Beneficial neurobiological effects of melatonin under conditions of increased oxidative stress

Aerobic organisms consistently sustain molecular abuse because of oxidative stress. Oxidative stress is a consequence of oxygen (O₂) being converted to semi-reduced toxic species including the superoxide anion radical (O₂^-̇), hydrogen peroxide (H₂O₂) and the hydroxyl radical (·OH). Besides these oxygen-based reactive species, the O₂-̇ also rapidly combines with nitric oxide (NO·) to produce the peroxynitrite anion (ONOO^-), an agent with well defined neurotoxic actions. Furthermore, ONOO^- is converted to peroxynitrous acid (ONOOH) which can degrade into the ·OH or an agent with similar toxicity. How much of the O₂ used by aerobes is actually converted to reactive species is unknown, but the general consensus is on the order of 2-4% of the total O₂ inhaled. Once formed the toxic species may or may not be neutralized by a complex antioxidative defense system. Those that are not detoxified can mutilate essential macromolecules within brain cells, thereby diminishing their functional efficiency, or, in extreme cases, killing the cells via either necrosis or apoptosis. Despite its importance for essential organismal functions as well as for survival, the central nervous system is unexpectedly highly susceptible to oxidative insults. One reason for this is that the brain, although constituting roughly 2% of the body weight in humans, utilizes 20% of the total O₂ inhaled. Thus, proportionally it generates a large number to toxic radicals. Other reasons for the brain's high susceptibility to free radical damage include the fact that it contains large quantities of polyunsaturated fatty acids (PUFA) which are easily damaged (oxidized) by reactive species and, regionally at least, the nervous system contains high levels of iron and ascorbic acid both of which, under the some circumstances, can be strongly prooxidant. Thus, the brain, perhaps more than any other organ, is subjected to excessive oxidative damage over the course of a life time. This persistent bludgeoning of essential molecules in brain cells is believed to contribute to a variety of neurodegenerative diseases. This review briefly describes the role of free radicals in several models of neurodegeneration and summarizes the actions of a newly discovered antioxidant, melatonin, in reducing the damage done by toxic oxygen and nitrogen derivatives.