Excitotoxicity, oxidative stress, and the neuroprotective potential of melatonin

The brain consumes large quantities of oxygen relative to its contribution to total body mass. This, together with its paucity of oxidative defense mechanisms, places this organ at risk for damage mediated by reactive oxygen species. The pineal secretory product melatonin possesses broad-spectrum free radical scavenging and antioxidant activities, and prevents kainic acid-induced neuronal lesions, glutathione depletion, and reactive oxygen species-mediated apoptotic nerve cell death. Melatonin's action is thought to involve electron donation to directly detoxify free radicals such as the highly toxic hydroxyl radical, which is a probable end-product of the reaction between NO. and peroxynitrite. Moreover, melatonin limits NO.-induced lipid peroxidation, inhibits cerebellar NO. synthase, scavenges peroxynitrite, and alters the activities of enzymes that improve the total antioxidative defense capacity of the organism. Melatonin function as a free radical scavenger and antioxidant is likely facilitated by the ease with which it crosses morphophysiological barriers, e.g., the blood-brain barrier, and enters cells and subcellular compartments. Pinealectomy, which eliminates the nighttime rise in circulating and tissue melatonin levels, worsens both reactive oxygen species-mediated tissue damage and brain damage after focal cerebral ischemia and excitotoxic seizures. That melatonin protects against hippocampal neurodegeneration linked to excitatory synaptic transmission is fully consistent with the last study. Conceivably, the decreased melatonin secretion that is documented to accompany the aging process may be exaggerated in populations with dementia.